@article {pmid42228338,
year = {2026},
author = {Chaudhary, B and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and Vellingiri, B and Medhi, B and HariKrishnaReddy, D},
title = {Decoding neuroinflammation: the critical role of NLRP3 inflammasome in Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42228338},
issn = {1568-5608},
abstract = {The hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease, include tau tangles, amyloid-β (Aβ) plaques, cognitive impairment, and severe neuroinflammation. A key molecular mediator linking immunological activation and neurological pathology in AD is the NLRP3 inflammasome. This review explains the intricate role of the NLRP3 inflammasome in AD, including its structure, activation mechanisms, and regulatory signaling pathways. The pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that activate NLRP3 include oxidative stress, Aβ, mitochondrial dysfunction, ion fluxes, gut dysbiosis, and mitochondrial malfunction. Pro-inflammatory cytokines IL-1β and IL-18 are released when the inflammasome assembles with ASC and procaspase-1, leading to caspase-1 activation and pyroptosis. The article investigates both canonical and noncanonical pyroptosis pathways and provides detailed insights into how glial cells-specifically microglia and astrocytes-are involved in NLRP3-mediated neuroinflammation. It has been demonstrated that NLRP3 activation is modulated by several receptor-mediated signaling pathways, including NF-κB, TLR4, TREM2, purinergic, and MAP4K6, which intensify inflammatory responses in the AD brain. Furthermore, the review assesses preclinical and clinical research targeting NLRP3 and its upstream regulators, emphasizing potential treatment options as Simufilam, MCC950, OLT1177, and CY-09. This work highlights the therapeutic potential of the inflammasome and promotes the development of targeted anti-inflammatory treatments to ameliorate AD pathology by elucidating the molecular mechanisms linking NLRP3 to AD progression.},
}

@article {pmid42229579,
year = {2026},
author = {Wang, D and Fan, J and Wang, T and Tang, F and Yao, Q and Ye, X and Qi, X and Tian, M and Lin, X and Shi, J},
title = {Cerebellar rTMS ameliorates cognitive impairment in Alzheimer's disease: A randomized trial.},
journal = {Brain stimulation},
volume = {19},
number = {4},
pages = {103138},
doi = {10.1016/j.brs.2026.103138},
pmid = {42229579},
issn = {1876-4754},
abstract = {BACKGROUND: Developing effective neuromodulatory therapies for Alzheimer's disease (AD) is a critical unmet need. While repetitive transcranial magnetic stimulation (rTMS) shows promise, its optimal targets and mechanisms remain incompletely understood. The cerebellum, a key modulator of large-scale brain network dynamics, represents a novel therapeutic target for addressing the distributed cognitive network dysfunction in AD.

OBJECTIVE: This study aimed to evaluate the cognitive efficacy and safety of cerebellar rTMS in AD and to elucidate its potential mechanism of action through the lens of structural network topology.

METHODS: In this randomized, double-blind, sham-controlled trial, patients with AD were assigned to receive active or sham rTMS targeting the bilateral cerebellar Crus II region. Cognitive assessments were conducted at baseline, post-treatment (4 weeks), and at a 12-week follow-up. Diffusion tensor imaging (DTI) was employed to analyze changes in whole-brain structural network topology.

RESULTS: Compared to the sham group, the active rTMS group demonstrated significantly greater improvement in global and domain-specific cognitive function at 4 weeks, with benefits sustained at the 12-week follow-up. Response rates on the MMSE and MoCA were also significantly higher in the active group. Neuroimaging revealed that active rTMS enhanced global network efficiency, indicated by significant increases in global/local efficiency and clustering coefficient, alongside a decreased characteristic path length, signifying an optimization toward small-world topology. Furthermore, treatment selectively enhanced nodal efficiency within core hubs of the default mode, frontoparietal, and salience networks. Critically, these structural improvements correlated with cognitive gains; increased nodal efficiency in the precuneus and posterior cingulate cortex was associated with improved episodic memory and visuospatial function.

CONCLUSION: Cerebellar rTMS is a safe and effective intervention that confers sustained cognitive benefits in AD. Its therapeutic mechanism likely involves the reinforcement of structural connectivity and enhanced integrative capacity within supraordinate cognitive networks, particularly the default mode network, via cerebello-cortical pathways.},
}

@article {pmid42229590,
year = {2026},
author = {Reddy-Mazzitello, RM and Alexander, J and Skawratananond, S and Sehar, U and Mukherjee, U and Brownell, M and Ballada, S and Reddy, PH},
title = {Associations Between Posttraumatic Stress and Comorbidities of Traumatic Brain Injury and Substance Use Disorders with Alzheimer's Disease in Older Veterans: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103188},
doi = {10.1016/j.arr.2026.103188},
pmid = {42229590},
issn = {1872-9649},
abstract = {Posttraumatic stress disorder (PTSD) exhibits high rates of comorbidity with Substance Use Disorders (SUDs) and Traumatic Brain Injury (TBI), especially in older adults who are subject to the effects of psychological trauma due to combat exposure, health-related and psychosocial outcomes, and aging. This narrative review explores the associations between PTSD and comorbidities of psychoactive substance abuse and traumatic brain injuries on the incidence of Alzheimer's disease (AD) in veterans aged 55>, according to existing literature. The account of genetic predisposition in reference to the presence of the Apolipoprotein e4 gene was also considered. Biomarkers of AD, including beta-amyloid and phosphorylated tau levels in cerebrospinal fluids (CSF), were analyzed in PTSD, TBI and SUD conditions. This review was conducted as a narrative summary utilizing three separate search engines. Inclusion of data was primarily determined by a single reviewer with a randomized 10 percent of 49 selected studies cross screened by a second reviewer. Two additional independent reviewers incrementally cross- checked the 49 included studies at full-text stages for accuracy and consistency. The literature review found that PTSD and comorbidities of TBI and SUD may share increased incidence of AD and related dementia, however, a causal relationship cannot be implied. Conflicting results on CSF biomarker trends for each comorbidity and complications arising from genetic predispositions indicate a need for future studies to clarify the relationship between PTSD comorbidities on the onset of AD. Expanded biomarker analysis has not yet been assessed. Implications of this review may lead to alternative treatment and care methods for older adults/veterans suffering from psychological impairment to prevent the formation of comorbidities and lower existing elevated risks for AD onset and progression.},
}

@article {pmid42229733,
year = {2026},
author = {Kumari, N and Kumari, S and Sharma, P and Dhapola, R and Paidlewar, M and HariKrishnaReddy, D},
title = {From capillaries to cognition: decoding neurovascular unit dysfunction and cerebrovascular contributions in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118107},
doi = {10.1016/j.bcp.2026.118107},
pmid = {42229733},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD), classically defined by abnormal amyloid-β and tau aggregation, is now also understood to profoundly disturb the brain's cerebrovascular system and the integrity of the neurovascular unit (NVU). An ever-growing body of evidence points to NVU dysfunction and neurovascular unit deficits as major contributors to AD pathology. NVU comprises neurons, glial cells, endothelial cells, and pericytes, which together orchestrate cerebral blood flow in the CNS and help maintain the structural and functional integrity of the blood-brain barrier (BBB). Its disruption increases neuronal damage and impairs clearance mechanisms in AD. Interactions between pericytes, astrocytes, smooth muscle cells, neurons, microglia, and NVU endothelial cells support cerebral perfusion, BBB integrity, and metabolic homeostasis. Major pathophysiological events involved in the development of early BBB leakage and neurovascular uncoupling in AD include endothelial impairment, breakdown of tight junctions, thickening of the basement membrane, degeneration of pericytes, and astrogliosis. Activated astrocytes and microglia further exacerbate NVU injury by releasing inflammatory mediators and ROS. Numerous molecular signaling cascades, including PI3K/Akt/mTOR, MAPK/ERK, and NF-κB pathways, are implicated in mechanistic interplay among metabolic perturbations, neuroinflammatory responses, and vascular endothelial damage. Emerging NVU-targeted therapeutic strategies include anti-inflammatory, antioxidant, and vasculoprotective drugs intended to restore BBB integrity, preserving neurovascular coupling, and promoting the removal of amyloid-β. This review synthesizes preclinical and clinical evidence elucidating mechanisms by which capillary-level perturbations lead to cognitive decline, while discussing therapeutic interventions aimed at restoring NVU integrity and preserving BBB architecture. The delineation of cerebral involvement in AD provides support for a potential for timely diagnosis and innovative approaches for treatment.},
}

@article {pmid42229832,
year = {2026},
author = {Singh, VB and Gupta, S and Sella, RN},
title = {Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127043},
doi = {10.1016/j.ijpharm.2026.127043},
pmid = {42229832},
issn = {1873-3476},
abstract = {Alzheimer's disease is driven in part by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Despite various attempts, therapeutic translation remains limited by inefficient delivery of bioactive molecules to neuronal cells. This study presents a surface-engineered extracellular vesicle (EV) platform designed for targeted peptide delivery, assessing its neuroprotective efficacy in an in vitro model of Alzheimer's disease. EVs were obtained from NIH/3T3 cells expressing Lamp2b-RVG and were surface-modified with the β-sheet breaker peptide H102 through CP05-CD63 affinity binding. ATR-FTIR, SERS Raman spectroscopy, high-resolution transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurements, and EV marker profiling demonstrated successful peptide conjugation and vesicle integrity. Aggregated Aβ25-35 was utilized to assess neuronal toxicity in NGF-differentiated PC-12 cells. Peptide-modified EV demonstrated effective, time-dependent cellular uptake and significantly improved cell viability while decreasing membrane damage and intracellular reactive oxygen species levels in comparison to Aβ-treated controls. Treatment with Peptide-modified EV normalized the expression of key genes associated with Alzheimer's, such as APP, Bax, Sirt1, and Stat1, suggesting a coordinated modulation of amyloidogenic, apoptotic, oxidative, and inflammatory pathways. The results indicate that surface-engineered EVs facilitate efficient neuronal delivery of therapeutic peptides and offer multi-level cytoprotection against Aβ-induced neurotoxicity. This study emphasizes the capability of peptide-decorated EV as a multifunctional nanocarrier system for the treatment of Alzheimer's disease.},
}

@article {pmid42230432,
year = {2026},
author = {Liao, Y and Ye, S and Zhao, L and Zhou, M and Wen, Y and Zhu, Y and Huang, J and Zhang, L and Zhang, X and Guo, P and Xie, Y},
title = {Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42230432},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, hyperphosphorylated Tau accumulation, and chronic neuroinflammation, with microglial function playing a crucial role in modulating these pathological cascades. The microglial receptor TREM2 has emerged as a key regulator of microglial responses to AD-related pathology, and gain-of-function strategies targeting TREM2 have shown substantial therapeutic potential in preclinical models. However, outcomes of these strategies on Aβ and Tau pathologies have exhibited marked heterogeneity across studies, and no systematic integration of the relevant evidence so far. This deficiency has substantially hindered the rational development and clinical translation of TREM2-targeted therapeutic strategies. The objective of this study is to evaluate the effects of TREM2-targeted interventions on Aβ and Tau pathologies in AD animal models. A systematic search of PubMed, Embase, and Cochrane Library identified studies using AD animal models with TREM2-targeted interventions and reporting Aβ or Tau outcomes. This review was registered in PROSPERO (CRD420251131147). A total of 12 studies were included, with overall moderate risk of bias, mainly due to inadequate randomization and blinding. In APP/PS1 mice, TREM2 overexpression significantly reduced Aβ plaque number (SMD = - 0.87; 95% CI, - 1.28 to - 0.47) and plaque area (SMD = - 0.98; 95% CI, - 1.46 to - 0.50), with more pronounced effects observed in younger mice (≤ 7 months), where reductions in insoluble Aβ42 were also observed; phosphorylated Tau levels decreased as well. TREM2 agonist antibodies also reduced Aβ plaque number (SMD = - 2.03; 95% CI, - 2.83 to - 1.24). However, effects on Aβ plaque area, insoluble and soluble Aβ isoforms levels were inconsistent. Antibody treatment also attenuated Tau pathology and Aβ pathology in certain models, including 5XFAD mice or Tau transgenic mice. In addition, both TREM2 overexpression and agonist antibodies could reverse the cognitive impairment of AD animal models. This systematic review and meta-analysis provides the first comprehensive synthesis of preclinical evidence supporting TREM2 gain-of-function modulation as an AD therapeutic strategy targeting both Aβ and Tau pathologies. Our findings reveal that therapeutic efficacy is governed by disease stage, model pathological complexity, and intervention mode. These insights highlight the need for developing stage-specific and pathology-stratified strategies in translational research, establishing TREM2 as a condition-dependent yet promising immunotherapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
Humans
Disease Models, Animal

@article {pmid42230965,
year = {2026},
author = {Jörg, M and Walz, L and Nathal, S and Kristen, M and Lietz, C and Müller, M and Nguyen, VTT and Ruffini, N and Winz, ML and Gerber, S and Endres, K and Helm, M and Friedland, K},
title = {Sex-specific regulation of angiogenin in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42230965},
issn = {1476-5578},
support = {TRR319 RMaP (Project Id 439669440) TPB05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; TRR319 RMaP (Project Id 439669440) TP A05//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5'-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets (n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5'-tiRNA[Gly-GCC]. Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.},
}

@article {pmid42231842,
year = {2026},
author = {Wiechmann, D and Günes, A and Kerz, E and Qiao, Y and Köhne, M and Sprick, U},
title = {Connected-speech digital biomarkers for monitoring transcranial pulse stimulation in Alzheimer's disease: A pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456294},
doi = {10.1177/13872877261456294},
pmid = {42231842},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique with potential to attenuate cognitive decline. Sensitive digital endpoints are needed to quantify intervention-related changes.ObjectiveTo develop and validate connected-speech-derived digital biomarkers as a longitudinal framework for monitoring TPS treatment response in AD.MethodsIn this open-label, single-arm pilot study, 32 patients with AD were compared to cognitively healthy controls. A three-stage framework was implemented: (1) machine-learning classification using linguistic features to derive a parsimonious biomarker panel; (2) construction of a Speech Composite Index (SCI) calibrated against the CERAD total score (CTS); and (3) longitudinal SCI tracking in a sub-cohort receiving TPS.ResultsThe classifier discriminated AD from controls with an AUROC of 0.879 and an F1-score of 0.825. The SCI showed strong convergent validity with global cognition (CTS: r = 0.76, p < 0.001; MMSE: r = 0.76, p < 0.001) and executive function (Stroop interference: r = -0.51, p = 0.015). Longitudinal modeling demonstrated a significant positive deviation from a CERAD-based progression reference (β_time = 0.057 z-units/month, p = 0.013), indicating relative stabilization of speech performance. Individual trajectories were heterogeneous (range -0.053 to +0.336) without significant demographic associations.ConclusionsConnected-speech-derived digital biomarkers can serve as scalable longitudinal endpoints for neuromodulatory interventions in AD. The SCI captures treatment-related dynamics and may support response stratification. Further validation in larger, sham-controlled multicenter studies is needed to establish clinical utility and specificity to TPS.},
}

@article {pmid42231857,
year = {2026},
author = {Rashidi-Ranjbar, N and Churchill, NW and Jerkic, M and Zomorrodi, R and Rotstein, O and Schneider, R and Andreazza, AC and Rajji, TK and Graham, SJ and Munoz, DG and Fornazzari, L and Lim, L and Norris, M and Schweizer, TA and Fischer, CE},
title = {A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453911},
doi = {10.1177/13872877261453911},
pmid = {42231857},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.},
}

@article {pmid42231859,
year = {2026},
author = {Tsutsui, S and Stepanchuk, AA and Stys, JP and Black, SAG and Templeton, GW and Greiner, R and Stys, PK},
title = {Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453512},
doi = {10.1177/13872877261453512},
pmid = {42231859},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome development; however, it is also now apparent that early treatment maximizes the benefits of these drugs. Therefore, it is important to develop reliable methods of disease detection, preferably from an easily accessible matrix such as blood.ObjectiveTo develop a method for detecting AD from circulating white blood cells using spectral confocal microscopy.MethodsUsing K114-stained wild type and 5xFAD transgenic mouse cortical sections as proof-of-principle, spectral imaging of K114 fluorescence coupled with a signal processing/machine learning pipeline (spectral wavelet decomposition, dimensionality reduction, support vector machine classifier) can reliably distinguish non-plaque background parenchyma in the two strains. We then performed immunoprecipitation of Aβ from peripheral blood mononuclear cells (PBMCs) obtained from non-neurological controls and histopathologically-proven AD cases. We spectrally imaged the immunobeads labeled with K114, then used similar machine learning methods to classify control versus AD samples.ResultsNormal-appearing non-plaque 5xFAD background was reliably distinguished from wild type mouse brain. We could also classify AD with a high degree of reliability (area under the receiver operating curve = 0.95, p = 6.1e-5) and predict neuropathological scores from these blood elements (R = 0.89).ConclusionsOur spectral imaging method, together with automated machine learning analysis of spectral micrographs, using readily obtainable PBMCs from blood, represents a potentially useful approach for detection of AD in living subjects.},
}

@article {pmid42231879,
year = {2026},
author = {Nibila, Y and Sivagami, M},
title = {Artificial intelligence techniques for classification of Alzheimer's disease using neuroimaging data: a review.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1748985},
pmid = {42231879},
issn = {2624-8212},
abstract = {Alzheimer's disease (AD) is a gradually advancing brain disorder marked by memory impairment. The incurable, progressive nature of the disease leads to the dementia stage. Treatment is effective in the early stage, and it can be controlled but not cured. Artificial Intelligence (AI) learning models are used in medical science to detect and classify diseases into specific categories. Features are extracted from medical images and trained using AI learning models to perform an accurate diagnosis of AD. Recent advancements in machine learning (ML) and deep learning (DL) models have demonstrated significant potential in identifying AD across various data modalities, including neuroimaging, genetic information, and clinical assessments. This study focuses on the application of advanced ML and DL techniques in the identification and classification of AD, including regression models, decision trees, random forests, support vector machines (SVMs), k-nearest neighbors (KNNs), ensemble models, convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). Each model is analyzed for its strengths, limitations, and performance metrics, with particular emphasis on the importance of data preprocessing and augmentation techniques to improve model accuracy and robustness. The review highlights that multimodal approaches, particularly the fusion of MRI and PET data, enhance classification accuracy compared to single-modality models. Additionally, transfer learning techniques have shown promise in overcoming data limitations by leveraging pretrained models. The review also highlights the critical role of evaluation metrics in assessing model performance, emphasizing the need for a diverse set that includes accuracy, precision, recall, F1-score, and Cohen's Kappa. The study identifies gaps in the current literature, including underreporting of certain metrics and the need for more comprehensive evaluations, and provides recommendations for future research. Finally, this study discusses the challenges and opportunities in the field, including improving model generalizability, enhancing interpretability, advanced data preprocessing and augmentation, integration with clinical workflows, and multimodal data fusion. This review provides consolidated information that may be useful for researchers, clinicians, and data scientists, offering insights into current trends, challenges, and future research directions in AI-driven AD detection.},
}

@article {pmid42221153,
year = {2026},
author = {Nitrini, R},
title = {Diagnosis of Alzheimer's disease in asymptomatic individuals: a historical perspective.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e2026487},
pmid = {42221153},
issn = {1980-5764},
abstract = {The diagnosis of Alzheimer's disease (AD) based on biomarkers of the pathological process represents a significant change from previous criteria, which required the presence of dementia for AD diagnosis. These new criteria create difficulties in disclosing the diagnosis of AD to asymptomatic individuals. A similar example exists in the history of cognitive and behavioral disorders, where the risk of developing dementia paralytica (DP), a form of neurosyphilis (NS), could be detected even in the asymptomatic phase. Treatment in this phase of DP or in its early symptomatic phase was successful due to the discovery of new therapeutic modalities and new evolutionary biomarkers, which are not yet widely available in AD. This type of biomarker was very important in NS and will certainly be in AD, allowing for faster and less expensive clinical trials.},
}

@article {pmid42221535,
year = {2026},
author = {Kogan, M and Frame, LA and Fahim Devin, M and Prather, C and Alchalabi, T and Ashraf, U and Darling Luczak, B and Fine, H and Ifateyo, A and Ledenac, M and Novak, SS and Yakel, J},
title = {The Integrative Personalized Functional Medicine Approach to Reverse Cognitive Decline: Academic Experience of the First 51 Patients Case Series.},
journal = {Global advances in integrative medicine and health},
volume = {15},
number = {},
pages = {27536130261452680},
pmid = {42221535},
issn = {2753-6130},
abstract = {Background: Alzheimer's disease (AD) and related dementias remain major public health challenges with limited treatment options. Personalized, multimodal integrative approaches have emerged as potential strategies for patients with mild cognitive impairment (MCI) and early-stage AD. Purpose: To describe outcomes from the first 51 participants enrolled in an academic integrative functional medicine program for cognitive decline. Research Design: Retrospective case series, chart analysis. Study Sample: Participants with MCI or AD enrolled at the GW Center for Integrative Medicine (n=51, 2017-2025); 22 remained in the program for ≥2.5 years for long-term cognitive analyses. Data Collection and/or Analysis: Participants underwent serial cognitive assessments [Montreal Cognitive Assessment (MoCA) and/or Boston Cognitive Assessment (BOCA), subset also completing CNS-Vitals and SLAMs at variable intervals]. MoCA was the prespecified primary outcome. Interventions included dietary modification, time-restricted eating, exercise, cognitive training, sleep optimization, individualized supplementation, hormonal management, and 40 Hz gamma-frequency sensory stimulation. Exploratory measures included volumetric brain MRI and Alzheimer's blood biomarkers (Aβ42/Aβ40, p-tau217, NfL) in a subset. Outcomes were summarized descriptively without formal statistical analyses. Results: Among participants with ≥2.5 years of follow-up, mean MoCA increased from 21.7 to 22.5, and 73% (16/22) demonstrated improvement (≥2-point increase) or stabilization (-1 to +1 points). Attrition was high; 29/51 discontinued within the first year, most commonly due to cost, program complexity, and lack of caregiver support. Conclusions: This program demonstrated encouraging preliminary findings of cognitive stabilization or improvement in participants with MCI or AD who remained enrolled. Controlled prospective trials are needed to determine efficacy and mechanisms.},
}

@article {pmid42221706,
year = {2026},
author = {Rangasamy, SB and Raha, S and Dasarathi, S and Pahan, K},
title = {Corrected Version: Sodium Benzoate, A Metabolite of Cinnamon and A Food Additive, Improves Cognitive Functions in Mice After Controlled Cortical Impact Injury.},
journal = {Journal of clinical & experimental immunology},
volume = {11},
number = {1},
pages = {11-26},
pmid = {42221706},
support = {I01 BX005002/BX/BLRD VA/United States ; IK6 BX004982/BX/BLRD VA/United States ; },
abstract = {Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults, and war veterans. Although the research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of effective therapy to halt the pathogenesis of brain injury. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and inhibits the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displayed substantial reduction in depression like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.},
}

@article {pmid42222332,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M},
title = {Genomic and proteomic conversion of brain ischemia to Alzheimer's disease.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1804251},
pmid = {42222332},
issn = {2296-634X},
abstract = {Despite many years of extensive research into the etiology and treatment of Alzheimer's disease, based on the importance of amyloid and tau protein as causative factors, these studies have stalled, have not brought any breakthroughs and, most importantly, have not led to any final conclusions. Therefore, the ineffectiveness of the above-mentioned actions and the pressure from the community of people affected by Alzheimer's disease forced the scientific community to change its way of thinking about the etiopathogenesis of this disease. This situation has prompted a group of scientists who have been studying the effects of brain ischemia for years to focus on post-ischemic changes, which-similarly to Alzheimer's disease-predominate in the hippocampus, leading to the development of amyloid plaques, neurofibrillary tangles and ultimately to dementia. In this context, it has been proposed that brain ischemia may play an important role in driving amyloid and tau protein pathology in the development of Alzheimer's disease. In this review, we present an update of extensive experimental and clinical studies conducted over several years on the role of brain ischemia in the neuropathogenesis of Alzheimer's disease. Current advances in understanding the ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer's disease-associated genes, including secretases, amyloid precursor protein, apoptosis, autophagy, mitophagy, tau protein, α-synuclein, apolipoproteins, LRP1, and RAGE. This article presents the relationship between genes which dysregulation is a result of brain ischemia and the cellular and tissue neuropathology characteristic of Alzheimer's disease and their proteins. These observations clearly indicate that, following brain ischemia, changes occur in the expression of Alzheimer's disease-associated genes and in the folding of disease-associated proteins such as amyloid, tau protein, and α-synuclein. This leads to massive neuronal death and disruption of the neuronal network, ultimately leading to the development of Alzheimer's disease-like dementia. Data indicate common genomic and proteomic factors in brain ischemia and Alzheimer's disease. It seems that the brain ischemia model may be useful in determining the role of folding proteins and their genes dysregulation in Alzheimer's disease. In the future, manipulation of genes and proteins associated with ischemia and ischemia-induced Alzheimer's disease will likely provide new hope for developing causal therapies that are urgently needed to prevent or treat Alzheimer's disease. The innovative/novel approach to the etiology of Alzheimer's disease presented in this review will provide stakeholders with a glimpse into the future.},
}

@article {pmid42222363,
year = {2026},
author = {Roamcharern, N and Yubolphan, R},
title = {Overcoming the blood-brain barrier in Alzheimer's disease: translational perspectives on advanced drug delivery platforms.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1810486},
pmid = {42222363},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents a growing public health challenge in aging societies. Despite extensive research efforts, currently approved therapies provide only limited symptomatic benefit and do not halt disease progression. A major obstacle to effective treatment is the blood-brain barrier (BBB), which severely restricts the brain delivery of most therapeutic agents. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome BBB-related limitations by enabling precise control over physicochemical properties such as size, surface characteristics, and material composition. These properties can improve drug solubility, stability, pharmacokinetics, and targeted brain accumulation while reducing systemic toxicity. However, efficient BBB penetration and clinically feasible translation remain major challenges. This review summarizes key design principles for nanoparticles intended for AD therapy and highlights representative platforms with translational considerations, particularly lipid-based and polymer-based nanoparticles. In addition, alternative delivery strategies-including nose-to-brain nanoparticle systems and nanoparticles exploiting receptor-mediated and adsorptive-mediated transcytosis, as well as synaptic dysfunction targeting-are discussed. Collectively, this review outlines current advances and future directions for nanoparticle-mediated therapeutic delivery in AD.},
}

@article {pmid42222852,
year = {2026},
author = {Kale, D and Ramachandran, I and Lakshmi, S and Elumalai, P},
title = {In-vivo evaluation of neuroprotective effect of methanolic extract of Turbinaria ornatacombined with AKG against aluminium chloride-induced Alzheimer's in Wistar rats.},
journal = {3 Biotech},
volume = {16},
number = {6},
pages = {240},
pmid = {42222852},
issn = {2190-572X},
abstract = {UNLABELLED: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by behavioral abnormalities and cognitive deterioration. In the current investigation, the preventive potential of a combination formulation of alkyl glycerol (AKG) and Turbinaria ornata methanolic extract against aluminum chloride (AlCl3)-induced neurotoxicity in Wistar rats was examined. Groups 1 (control), 2 (AlCl3, 100 mg/kg), 3 and 4 (AlCl3 + T. ornata methanolic extract at low and high doses, respectively), and 5 and 6 (AlCl3 + T. ornata methanolic extract + AKG at low and high dosages, respectively) were the six groups that were part of the experimental design. Compared with the AlCl3-treated group, animals receiving the combined treatment, particularly Group 6, showed a significant restoration of antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), along with a significant reduction in the lipid peroxidation marker malondialdehyde (MDA) in brain and liver tissues. Exposure to AlCl3 caused learning and memory deficits and markedly hampered spontaneous locomotor and exploratory behavior; these effects were mitigated with combination therapy. Additionally, both the cortex and the hippocampus showed changed expression of important genes involved in the amyloid precursor protein (APP) processing pathway, according to qRT-PCR study. The combined treatment groups demonstrated significant modulation of APP pathway-related gene expression relative to the AlCl3 group, indicating an association between the observed biochemical and behavioral improvements and molecular changes in this experimental model. Overall, the results imply that AlCl3-induced neurobehavioral, biochemical, and molecular changes may be lessened by administering T. ornata methanolic extract and AKG together. To identify the independent or synergistic impacts of each component, more research including individual treatment groups is necessary, as the study is restricted to assessing the effects of the combination treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04872-2.},
}

@article {pmid42223785,
year = {2026},
author = {Özkurt, Ç and Köse, S and Karasu, Ç and Kortholt, A and Kelicen-Uğur, P},
title = {Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42223785},
issn = {1573-6903},
mesh = {Animals ; *Autophagy/drug effects/physiology ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Glucosylceramidase/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; Humans ; Hippocampus/drug effects/metabolism ; Peptide Fragments ; Cell Line ; Lysosomes/metabolism/drug effects ; Signal Transduction/drug effects ; Recombinant Proteins/pharmacology ; },
abstract = {Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ1-42 oligomer-enriched assemblies (oAβ1-42), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.},
}

Animals
*Autophagy/drug effects/physiology
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/metabolism/drug therapy/pathology
*Glucosylceramidase/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism
Humans
Hippocampus/drug effects/metabolism
Peptide Fragments
Cell Line
Lysosomes/metabolism/drug effects
Signal Transduction/drug effects
Recombinant Proteins/pharmacology

@article {pmid42226198,
year = {2026},
author = {Lee, HJ and Hoe, HS},
title = {The CDK4/6 inhibitor abemaciclib attenuates cognitive impairment and neuroinflammation via DYRK1A in human tau transgenic mice.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01318-x},
pmid = {42226198},
issn = {1756-6606},
support = {RS-2024-00357857//National Research Foundation of Korea/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2024-00343370//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)/ ; H0501-25-1001//NIPA (National IT Industry Promotion Agency) to support digital medical devices for AI-based Neurodevelopmental disorders/ ; RS-2026-25492172//NRF/ ; },
abstract = {We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. In this study, we investigated the influence of abemaciclib treatment on neuroinflammation and cognitive function in 6- or 9-month-old PS19 mice, a P301S mutant tauopathy model. We found that abemaciclib administration suppressed microglial activation in 6-month-old PS19 mice, whereas astrocytic activation was partially attenuated in the entorhinal cortex but not in the hippocampus. In addition, abemaciclib treatment improved short-term and recognition memory and the dendritic spine formation in 6- and 9-month-old PS19 mice. More importantly, abemaciclib administration enhanced short-term and recognition memory in a DYRK1A-dependent manner in 6-month-old PS19 mice. Collectively, our results suggest that abemaciclib treatment alleviates neuroinflammatory responses and cognitive impairment through DYRK1A in 6- or 9-month-old human tau transgenic PS19 mice, highlighting how this multi-kinase-targeting drug could be leveraged for the treatment of neurodegenerative diseases.},
}

@article {pmid42227120,
year = {2026},
author = {Gillet, JN},
title = {Overinvestment in ultra‑rare APOE variants and highly speculative apoE-inhibitor docking risks undermining translational progress in sporadic Alzheimer's disease.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/07391102.2026.2671163},
pmid = {42227120},
issn = {1538-0254},
abstract = {Misclassification of ultra-rare and isoform-defining APOE variants, together with unsupported attempts to dock small-molecule 'inhibitors' to apolipoprotein E (apoE), continues to appear in the structural bioinformatics literature. Such inconsistencies stem from a broader misunderstanding of apoE as a highly flexible, two-domain protein with extensive intrinsically disordered regions (IDRs), a context essential for interpreting sequence variation. A recurring issue is the treatment of the pathogenic ε4 and protective ε2 substitutions as independent rare variants rather than as the canonical APOE isoform-defining polymorphism, a misinterpretation arising, for instance, from inconsistent minor-allele-frequency filtering and leading to overinterpretation of ultra-rare substitutions lacking established clinical relevance. Likewise, no experimental evidence supports stable interactions between apoE and small 'inhibitors' such as donepezil or other acetylcholinesterase drugs that provide only symptomatic benefit in Alzheimer's disease (AD). Docking such small ligands to apoE-frequently using incompatible homology models and outdated molecular-dynamics force fields ill-suited for proteins with large IDRs (e.g. AMBERff03)-tends to generate simulation-artifact cavities and non-biological ligand poses; compounding this, ligand protonation is frequently misassigned, such as the neutral state often attributed to donepezil, leading to meaningless structure-activity relationships. Collectively, these issues risk obscuring the well-established genetic architecture of APOE-associated AD and highlight the need for methodological rigor in in-silico structural modeling.},
}

@article {pmid42227129,
year = {2026},
author = {Andreev, AI and Neganova, ME and Aleksandrova, YR and Salikhova, DI and Belousova, EV and Shedenkova, MO and Sudina, AK and Maksimov, YM and Orlova, EA and Lapshina, MA and Popov, VS and Ahremenko, EA and Goldshtein, DV and Ustyugov, AA and Nebogatikov, VO},
title = {[Glial Progenitor Cell Therapy Improves Mitochondrial Function in the Hippocampus of 5xFAD Mice, but Does Not Restore the Multiscale Structure of Behavioral Stress Response].},
journal = {Molekuliarnaia biologiia},
volume = {60},
number = {2},
pages = {328-344},
doi = {10.7868/S3034555326020096},
pmid = {42227129},
issn = {0026-8984},
abstract = {Cell therapy is increasingly used to treat a variety of medical conditions, including cancer, immune system disorders, and neurodegeneration. Stem cells secrete growth factors, signaling molecules, and extracellular vesicles, that can be used to treat neurological diseases and promote neuronal regeneration. Transgenic 5xFAD mice, which are a model for Alzheimer's disease (AD), were used in this study. The mice were 7 months old and received retro-orbital injections of glial progenitor cells (GPCs) once a week for 4 months. At 11 months, their behavior was analyzed using a multichannel actigraphy system. Brain tissues from the cortex, hippocampus, and midbrain were collected for postmortem analysis of mitochondrial respiratory chain enzyme activity. The results showed that the GPCs injection significantly improved the response of the hippocampal p2 mitochondrial fraction in 5xFAD mice to succinate, reaching a level observed in control animals. A similar trend was also observed for the cytochrome c oxidase complex. The oxygen consumption rate of mitochondria did not differ from that of clinically healthy mice after ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride administration. A similar decrease in the efficiency of the electron transport chain was detected in the midbrain of 5xFAD mice, but no recovery was observed after GPCs treatment. Behavioral differences between non-transgenic and transgenic groups were observed in a multiparameter analysis using the actigraphy system. The behavior of transgenic mice in the treated and untreated groups was similar, while the behavior of non-transgenic mice varied. Additional analysis of locomotor activity and transient events in particular revealed that the activity of the GPCs-treated 5xFAD mice was differed fundamentally compared to other groups. Specifically, GPCs-treated mice exhibited greater number of transitions between intermediate activity states. In contrast, untreated mice showed transitions between extreme activity states, such as from low to high activity or vice versa. These findings suggest that changes in behavior and activity of the AD mice may be associated not only with hippocampal dysfunction, but also with disruptions in midbrain structures.},
}

@article {pmid42227398,
year = {2026},
author = {Wu, X and Zhang, K and Kan, C and Sheng, S and Jing, D and Han, F and Sun, X},
title = {Transmembrane Proteins in Neurodegeneration: Pathophysiology from Alzheimer's to Parkinson's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X451846260403084025},
pmid = {42227398},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), represent a growing global health burden due to aging populations. These disorders are characterized by progressive neuronal dysfunction, protein aggregation, synaptic impairment, and neuronal loss. Transmembrane proteins, which regulate signal transduction, material transport, and cell communication, have emerged as key contributors to disease pathogenesis. In AD, amyloid precursor protein processing, N-methyl-D-aspartate receptor overactivation, and microglial receptor signaling drive β-amyloid accumulation, excitotoxicity, and neuroinflammation. In PD, α-synuclein aggregation, dopamine receptor dysregulation, mitochondrial dysfunction, and impaired iron homeostasis disrupt neuronal and synaptic integrity. Despite differences in clinical manifestations, both AD and PD share common mechanisms involving abnormal protein folding, altered calcium signaling, and oxidative and endoplasmic reticulum stress, largely mediated by transmembrane proteins. These shared pathways highlight the interconnected nature of these devastating conditions. These proteins also provide opportunities for therapeutic targeting and biomarker development. Current strategies include secretase inhibitors, N-methyl-D-aspartate receptor modulators, dopamine agonists, and emerging approaches targeting α-synuclein and other misfolded proteins. While challenges remain in achieving selectivity, delivery, and clinical efficacy, advances in molecular biology underscore the potential of transmembrane proteins as critical targets for diagnosis and treatment. Ongoing research continues to unravel their complex roles, and future studies will further elucidate their precise involvement in disease progression, offering hope for new interventions. This comprehensive review summarizes current knowledge on the structural and functional roles of transmembrane proteins in AD and PD, their contributions to shared pathological mechanisms, and their potential as biomarkers and therapeutic targets.},
}

@article {pmid42227403,
year = {2026},
author = {Yang, Z and Hou, X and Tan, Y and Tang, L and Ke, Z and Hu, Z and Ye, Q and Meng, H and Xu, Y and Chen, H},
title = {Neuro-navigated rTMS Targeting Left Angular Gyrus Promotes White-Gray Matter Remodelling to Improve Cognitive Function in Amnestic Mild Cognitive Impairment Patients: Evidence for Early Alzheimer.s Intervention.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438627260121063828},
pmid = {42227403},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neuromodulation technique, has been increasingly applied in early intervention for amnestic Mild Cognitive Impairment (aMCI). However, the mechanism of changes in brain structure after rTMS treatment remains unclear.

METHODS: A total of 54 aMCI patients received neuro-navigation rTMS targeting the left angular gyrus for 4 weeks (rTMS group: n=28; sham group: n=26). All participants received multimodal MRI and cognitive assessments before and after rTMS. A white matter network was constructed, and Local Diffusion Homogeneity (LDH) was calculated to analyse white matter differences. Surface-based morphometry was used to detect cortical changes. In addition, the correlation between these structural alterations and improved cognitive function was analysed.

RESULTS: After rTMS, general cognitive function and episodic memory of aMCI patients significantly improved. Assortativity improved (P=0.039) while hierarchy decreased (P=0.036). Lower LDH was detected in the right hippocampus cingulum fasciculus, left inferior longitudinal fasciculus, right inferior/superior cerebellar peduncle, and right cingulum gyrus. The sulcus depth of the left medial orbitofrontal cortex, left superior frontal/parietal cortex, left middle/inferior temporal cortex, and right lateral occipital cortex was decreased. Improved general cognition was negatively correlated with decreased sulcus depth in left inferior temporal cortex (R=-0.585, P=0.001) and left superior parietal cortex (R=-0.447, P=0.017). Improved memory was negatively correlated with altered LDH in the right inferior cerebellar peduncle (R=-0.427, P=0.037).

DISCUSSION: Our study shows that neuro-navigated rTMS targeting the left angular gyrus can improve cognitive function and mood symptoms in aMCI patients by impacting brain structures, offering new biological evidence for its potential as an early AD intervention.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus improves aMCI cognition, linked to specific brain structural changes, supporting its early intervention value.},
}

@article {pmid42227483,
year = {2026},
author = {Shankar, M and Tiwari, P and Dubey, S},
title = {Phosphodiesterase-5 Inhibitors in Neurodegenerative Diseases: A Path to Cognitive Rescue.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037397181251204145349},
pmid = {42227483},
issn = {1875-5550},
abstract = {Phosphodiesterase type 5 inhibitors (PDE5-Is) have emerged as potential therapeutic agents for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Originally developed for cardiovascular disorders, PDE5-Is have gained significant attention for their neuroprotective effects due to their ability to modulate intracellular signaling pathways. These inhibitors exert their effects by increasing nitric oxide synthase expression, elevating cyclic guanosine monophosphate (cGMP) levels, and activating protein kinase G (PKG), leading to improved synaptic plasticity, neuronal survival, and cognitive enhancement. By targeting these molecular pathways, PDE5-Is help regulate neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis, which are key pathological features of neurodegenerative disorders. Several preclinical studies have demonstrated that PDE5-Is can reduce neuroinflammation, enhance neurogenesis, and improve mental performance in animal models of AD, PD, and MS. Additionally, these agents have shown promise in mitigating β-amyloid and tau pathology in AD, improving dopamine signalling in PD, and exerting immunomodulatory effects in MS. Furthermore, emerging research suggests that PDE5-Is may protect against neuronal cell death and improve cognitive function following cerebral ischemia by enhancing cerebral blood flow, reducing excitotoxicity, and promoting neurovascular coupling. Despite these promising findings, the clinical translation of PDE5-Is for neurodegenerative diseases remains in its early stages. Challenges, such as blood-brain barrier permeability, optimal dosing strategies, and long-term safety, must be addressed through further research. Nevertheless, given their multifaceted mechanisms of action, PDE5-Is represent a novel and exciting therapeutic approach that warrants deeper investigation in both preclinical and clinical settings for the treatment of neurodegenerative diseases.},
}

@article {pmid42227779,
year = {2026},
author = {Sharma, DK and Prasad, CS},
title = {Chitosan-based nanocarriers in Alzheimer's disease therapy: Recent developments and future perspectives.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/1061186X.2026.2683967},
pmid = {42227779},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a neurological condition that worsens with time and causes behavioral problems, memory loss, and cognitive decline. It is a major global health concern. Alzheimer's complexity and the blood-brain barrier (BBB) limit effective disease-modifying treatments despite extensive research. The primary goal of conventional pharmacotherapies is to relieve symptoms; however, they frequently have low absorption, a short half-life, and peripheral adverse effects. The use of anti-Alzheimer medications in nanoparticles (NPs) is a potential remedy for these issues. Although many NPs are biocompatible and nontoxic, many are not biodegradable, making them unsuitable for CNS targeting. Chitosan (CS)-based NPs stand out among polymeric nanocarriers as stable, biodegradable delivery systems for central nervous system drugs. In this review, we examine the design, mechanisms of BBB penetration, drug-loading capacity, controlled-release behaviour, and therapeutic efficacy of CS-based delivery platforms, including nanoparticles, nanogels, lipid nanoparticles, polymeric micelles, nanoemulsions, and acetylcholinesterase inhibitor-loaded systems. Furthermore, the benefits of CS-based systems, including improved brain bioavailability, reduced toxicity, intranasal delivery, and support for multifunctional and stimuli-responsive therapeutics, are highlighted. All things considered, chitosan-based drug delivery systems offer a flexible and promising strategy for enhancing AD treatment results.},
}

@article {pmid42216640,
year = {2026},
author = {Kong, Y and Lv, X and Yang, Y and Li, Q and Dai, C and Lin, X and Liu, J and Li, J},
title = {Lactobacillus mucosae Reduces Neuronal Oxidative Stress in Alzheimer's Disease via the Regulation of CB2 Signaling.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {5},
pages = {48598},
doi = {10.31083/JIN48598},
pmid = {42216640},
issn = {0219-6352},
support = {Y20240038//Science and Technology Funds of Wenzhou/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/metabolism/drug therapy ; Male ; *Probiotics/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Disease Models, Animal ; *Receptor, Cannabinoid, CB2/metabolism/drug effects ; Mice, Transgenic ; Mice ; *Neurons/metabolism/drug effects ; *Lactobacillus ; },
abstract = {BACKGROUND: The probiotic Lactobacillus mucosae has been widely shown to have many positive effects. However, its neuroprotective effects and underlying mechanism in Alzheimer's disease (AD) remain elusive.

METHODS: Male APP/PS1 mice were treated for 4 weeks with L. mucosae WMU007, followed by the evaluation of cognitive function, neuronal damage, amyloid-β (Aβ) deposition, and Tau phosphorylation. RNA-seq coupled with Gene Ontology (GO) enrichment analysis implicated L. mucosae WMU007 in modulating oxidative stress in this AD model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and qPCR were performed to identify the specific mechanism by which this probiotic suppresses oxidative stress in the pathogenesis of AD. In addition, we quantified the levels of classical oxidative stress markers, such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 4 (GPX4). We also examined the expression of cannabinoid receptor type 2 (CB2) and its key downstream regulators in the redox pathway, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), in both animal and cellular models.

RESULTS: Our results showed that treatment with L. mucosae WMU007 significantly decreased cognitive impairment, neuronal damage, Aβ deposits, and Tau phosphorylation in APP/PS1 mice. Activation of CB2 was identified as the key mechanism by which L. mucosae WMU007 reduces oxidative stress in AD. In addition, L. mucosae WMU007 reduced oxidative stress and increased the levels of CB2 pathway-related proteins in vivo and in vitro.

CONCLUSIONS: These results indicate that L. mucosae WMU007 confers neuroprotection in AD by targeting CB2-mediated oxidative pathways, highlighting its therapeutic potential as a novel probiotic intervention.},
}

Animals
*Oxidative Stress/drug effects/physiology
*Alzheimer Disease/metabolism/drug therapy
Male
*Probiotics/pharmacology/administration & dosage
*Signal Transduction/drug effects
Disease Models, Animal
*Receptor, Cannabinoid, CB2/metabolism/drug effects
Mice, Transgenic
Mice
*Neurons/metabolism/drug effects
*Lactobacillus

@article {pmid42216664,
year = {2026},
author = {Wen, T and Zhu, T and Zhou, LY and Ran, Z and Chen, L and Wang, WJ},
title = {Bibliometric analysis of natural medicine in the treatment of Alzheimer's disease: Trends, hotspots, and emerging research fields.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451887},
doi = {10.1177/13872877261451887},
pmid = {42216664},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder whose global prevalence continues to rise, yet treatment options are still limited. Natural medicines, with their potential for multi-target intervention, have become a key direction in AD drug development. However, a systematic overview of research trends in this field based on bibliometric methods is currently lacking.ObjectiveThis study aims to summarize research progress on natural medicines for AD treatment using bibliometric analysis and to identify future research hotspots and trends.MethodsRelevant publications were retrieved from the Web of Science Core Collection. Data visualization and analysis were conducted using VOSviewer, CiteSpace, and R.ResultsA total of 3800 publications were included, involving contributions from 108 countries/regions, 4024 institutions, 18,729 authors, and 706 journals. Publication output showed steady growth, with China and India as the leading contributing countries. Institutions such as the Chinese Academy of Sciences and Kyung Hee University demonstrated high productivity and influence. The research focus has shifted from initial clinical pharmacology and molecular pathology to exploring multi-target mechanisms of natural medicines through network pharmacology and molecular docking. Promising natural agents include Ginkgo biloba, ginseng, curcumin, resveratrol, and Centella asiatica.ConclusionsResearch on natural medicines for AD has progressed steadily over the past two decades, with current emphasis on elucidating multi-target mechanisms using emerging technologies. However, clinical evidence remains limited. Future studies should strengthen multi-omics integration and clinical translation to foster innovative AD prevention and treatment strategies.},
}

@article {pmid42216879,
year = {2026},
author = {Pyun, J and Noor, A and Runwal, P and Mawal, C and Fuller, OK and Egan, CL and Febbraio, MA and Donnelly, PS and Short, JL and Bush, AI and Nicolazzo, JA},
title = {Cu(ATSM) Restores Blood-Brain Barrier Abundance of P-Glycoprotein and Improves Cognitive Function in the APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00252},
pmid = {42216879},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain. P-glycoprotein (P-gp), a key efflux transporter at the blood-brain barrier (BBB), plays a crucial role in the clearance of Aβ. Using the APP/PS1 mouse model of familial AD, this study investigated the effect of copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) on brain microvascular abundance and function of P-gp and the associated effects on exogenous Aβ clearance, brain amyloid burden, and cognitive function. Compared to vehicle-treated 10 month-old APP/PS1 mice, Cu(ATSM) (30 mg/kg/day for 56 days) restored brain microvascular P-gp abundance (24.1%) and Cu concentrations (229.8%) as well as significantly reduced brain cortical concentrations of human Aβ42 (hAβ42) (42.1%) in APP/PS1 mice. Cu(ATSM) treatment led to a trend toward improved brain clearance (11.9%) of [125]I-Aβ42 that was cortically injected into APP/PS1 mice compared to vehicle-treated APP/PS1 mice. Importantly, Cu(ATSM) treatment led to significantly improved (43.8% p = 0.0087) learning and long-term spatial memory in APP/PS1 mice, assessed by the Barnes maze paradigm. Inductively coupled plasma mass spectrometric analysis revealed increased Cu concentrations in brain microvessel-enriched fractions. In APP/PS1 mice, Cu(ATSM) restored brain microvascular P-gp abundance, which was associated with lowered cortical hAβ42, and improved long-term spatial memory, indicating neurovascular target engagement accompanied by amyloid lowering and behavioral benefit. Together with established BBB penetration and ongoing safety and tolerability evaluation in neurodegenerative populations, these findings propose Cu(ATSM) as a potential therapeutic application of biometal modulation targeting neurovascular dysfunction and Aβ burden in AD.},
}

@article {pmid42217307,
year = {2026},
author = {Sharma, S and Kumar, V and Arulsamy, S and Kumar, S and Wadhwa, P},
title = {An integrated in silico approach to identify pyridine-based AChE and BChE inhibitors for Alzheimer's disease.},
journal = {Computers in biology and medicine},
volume = {212},
number = {},
pages = {111765},
doi = {10.1016/j.compbiomed.2026.111765},
pmid = {42217307},
issn = {1879-0534},
abstract = {Among all the neural diseases Alzheimer's disease (AD) represents a major and critical global health challenge, along with limited diseases-altering therapeutic interventions efficacy. This study deploys collective approaches of in silico study which includes molecular docking, ADMET profiling, density functional theory (DFT), and MD simulations simulation to evaluate pyridine-based dual inhibitors which can target acetylcholinesterase (AChE PBD ID: 4EY7) and butyrylcholinesterase (BChE PDB ID: 6I0B). From a curated library of 55 ZINC-derived compounds, virtual screening using AutoDock Vina identified lead candidates exhibiting superior binding affinities (-11.5 to - 8.0 kcal/mol for AChE; - 10.9 to - 7.4 kcal/mol for BChE) compared to marketed drugs donepezil and tacrine. Compound 46 emerged as the top AChE inhibitor, while compound 49 demonstrated optimal BChE inhibition. DFT analysis at the B3LYP/6-31G(d) level revealed distinct electronic properties: compound 46 exhibited a wider HOMO-LUMO gap (5.32 eV) correlating with enhanced kinetic stability, whereas compound 49 displayed a narrower gap (5.10 eV) and elevated dipole moment, supporting target-selective binding. Extended MD simulations with 200 ns of total duration confirmed that compounds 46 and 49 (two complexes) have structurally stable conformations compared with each other; however, compound 49 was found to be thermodynamically more stable according to MM-PBSA predicted binding free energy (-54.96 ± 4.36 kcal/mol) than compound 46 (-44.73 + 4.85 kcal/mol). ADMET predictions showed good intestinal absorption and CNS permeability; however, it will be necessary to improve both the solubility of these compounds as well as their CYP3A4-related liability. This multi-tiered computational strategy was able to identify both compounds 46 and 49 as highly promising candidates for further experimental validation as dual cholinesterase inhibitors that will be incorporated into efforts to develop new AD treatment approaches.},
}

@article {pmid42217970,
year = {2026},
author = {Toma, C and Vujosevic, S},
title = {Optical coherence tomography and OCT-angiography in neurologic and neuro-ophthalmologic diseases: Current applications and future perspectives.},
journal = {Handbook of clinical neurology},
volume = {218},
number = {},
pages = {13-32},
doi = {10.1016/B978-0-443-22212-2.00022-7},
pmid = {42217970},
issn = {0072-9752},
mesh = {Humans ; *Tomography, Optical Coherence/methods/trends ; *Nervous System Diseases/diagnostic imaging ; *Eye Diseases/diagnostic imaging ; Retina/diagnostic imaging ; },
abstract = {Optical coherence tomography (OCT) and OCT-angiography (OCTA) have emerged as useful tools for noninvasive imaging in the neurologic field. This chapter elucidates their utility in detecting biomarkers for the diagnosis and monitoring of progression and response to treatment in different prevalent neurologic conditions. The retina, an extension of the central nervous system, presents a unique opportunity for monitoring brain pathology due to its accessibility. Through highly resolved scans of the retina and optic nerve, OCT and OCTA facilitate the identification of subtle clinical changes occurring during neuroinflammatory, neurodegenerative, and ischemic processes in disorders like multiple sclerosis, Alzheimer and Parkinson disease, anterior ischemic optic neuropathies, and papilledema. Peripapillary nerve fiber layer and macular internal retinal layer thickness on OCT, and vessel density in the superficial retina on OCTA seem to be the most sensitive parameters in detecting axonal injury and neurodegeneration. These metrics hold promise as surrogate markers for cerebral alterations. While OCT and OCTA show considerable potential, continued research is necessary to validate their reliability and clinical significance, considering potential confounding factors such as concurrent ophthalmic pathologies. Nonetheless, these advancements represent significant progress toward enhancing the diagnosis, management, and prediction of outcomes in various neuro-ophthalmic disorders.},
}

Humans
*Tomography, Optical Coherence/methods/trends
*Nervous System Diseases/diagnostic imaging
*Eye Diseases/diagnostic imaging
Retina/diagnostic imaging

@article {pmid42218511,
year = {2026},
author = {Lin, H and Zhang, Y and Ni, R and Wang, M and Men, J and Ge, J and Lu, J and Wang, J and Zhang, H and Yang, Y and Zhang, Z and Zhu, Y and Zhao, H and Yen, TC and Wang, J and Shi, K and Rominger, A and Guan, Y and Fang, M and Yu, J and Jiang, J and Zuo, C},
title = {White matter [18]F-florbetapir retention predicts cognitive decline and treatment response in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02098-1},
pmid = {42218511},
issn = {1758-9193},
support = {2022ZD0211606//STI2030-Major Projects/ ; 82021002, 82272039, and 82394434//National Natural Science Foundation of China/ ; },
abstract = {PURPOSE: White matter (WM) signal on [18]F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance remains unclear. This study aimed to characterize the trajectory, clinical significance, and biomarker correlates of normal-appearing white matter (NAWM) [18]F-florbetapir retention across the Alzheimer's disease (AD) continuum.

METHODS: We analyzed NAWM ¹⁸F-florbetapir retention in 672 participants across the AD continuum from the Alzheimer's Disease Neuroimaging Initiative and two Chinese cohorts. Longitudinal PET, plasma, and cerebrospinal fluid (CSF) biomarkers, as well as lecanemab treatment effects, were evaluated.

RESULTS: NAWM retention followed a distinct trajectory from cortical amyloid, increasing during preclinical stages and plateauing in symptomatic phases. Elevated NAWM ¹⁸F-florbetapir retention independently predicted cognitive decline, correlated with plasma p-tau217 and CSF p-tau/Aβ42 ratio, and showed significant reductions following lecanemab therapy. Combined assessment of cortical and NAWM PET improved diagnostic accuracy for amyloid positivity to 92%. NAWM retention also correlated strongly with plasma and CSF biomarkers in preclinical stages, and mediation analyses indicated that these fluid markers partly explained NAWM-cognition associations.

CONCLUSION: NAWM ¹⁸F-florbetapir retention represents a biologically valid and dynamic biomarker of AD progression, with potential utility for early detection, prognostication, and therapeutic monitoring.},
}

@article {pmid42218670,
year = {2026},
author = {Dong, Y and Xiao, X and Zhuang, XX and Wu, W and Fang, EF and Yang, G and Niu, Z and Lu, JH},
title = {AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2026.2679639},
pmid = {42218670},
issn = {1554-8635},
abstract = {Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.},
}

@article {pmid42220121,
year = {2026},
author = {Zhao, J and Tian, G and Qu, Y and Liu, Y and Wu, W and Dai, L and Zhang, G and An, F},
title = {Research Progress on Alzheimer's Disease with Classical Traditional Chinese Medicine Formulas.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018401009251117113526},
pmid = {42220121},
issn = {1875-5704},
abstract = {Alzheimer's disease (AD) is caused by complex pathological changes and is a problem that cannot be ignored by the global public health system. Its main clinical manifestations include progressive cognitive impairment, mental and psychological changes, and, in advanced stages, paralysis and loss of self-care ability. The economic and psychological burdens imposed on AD patients and their caregivers have been progressively exacerbating, while the annual expenditures on AD treatment by nations worldwide and by the United Nations have demonstrated a consistent upward trend rather than a decline. The treatment of AD remains challenging, with currently limited therapeutic options available. The advantages of the multi-target, multi-component, safe, and low-toxicity characteristics of Traditional Chinese Medicine (TCM) have attracted public attention, providing ideas for the prevention and treatment of AD and for the development of new drugs. In this study, 27 TCM formulas reported to exhibit preventive and therapeutic effects on AD in basic or clinical research were identified and summarized. TCM can intervene in the progression of AD by clearing Aβ deposition, inhibiting Tau phosphorylation, reducing neuroinflammation, mitigating mitochondrial dysfunction and oxidative stress, and regulating gut microbiota. This review aims to provide evidence for further exploring the role and potential mechanisms of TCM in the prevention and treatment of AD, and to offer insights for the development of new anti-AD drugs.},
}

@article {pmid42220134,
year = {2026},
author = {Singh, I and Dheek, M and Usmani, A and Chauhan, SB and Sinha, A},
title = {Development, Optimization, and Characterization of Donepezil Hydrochloride-loaded Emulsomes with Nigella Sativa Oil for the Treatment of Alzheimer's Disease.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026444242260514094253},
pmid = {42220134},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease is a progressive neurodegenerative disorder where conventional oral delivery of donepezil hydrochloride is limited by poor bioavailability and restricted brain access due to the blood-brain barrier. This study aims to develop an alternative nanocarrier-based delivery system to enhance therapeutic efficacy.

METHOD: Trestearin, phosphatidylcholine, and cholesterol formed a solid lipid core that was used to make emulsomes. TEM was used to characterize emulsomes, while FTIR spectroscopy was used for compatibility tests. The formulation was optimized using the 3-factor, 3-level Central Composite Design.

RESULT: The optimized emulsome formulation demonstrated a stable formulation with a mean particle diameter of 124 ± 3.25 nm, an entrapment efficiency of 74 ± 0.67%, a PDI of 0.209 ± 0.03, with a zeta potential of -0.130 mV. In vitro release study demonstrated a consistent drugrelease pattern, with 84 ± 1.24% of the medication released during the investigation.

DISCUSSION: Based on insights from the thesis, emulsomes incorporating Nigella sativa oil show enhanced neuroprotective potential due to the antioxidant and anti-inflammatory actions of thymoquinone. The intranasal route further supports improved brain targeting by bypassing the blood-brain barrier. The consistency of particle size, strong entrapment efficiency, and sustained drug release align with the reported advantages of emulsome-based formulations discussed in the thesis, reinforcing their promise as an effective approach for Alzheimer's treatment.

CONCLUSION: The central composite design optimization ensures a stable and effective delivery system for the donepezil hydrochloride-loaded emulsomes containing Nigella sativa oil with great potential for novel drug delivery in Alzheimer's disease.},
}

@article {pmid42220141,
year = {2026},
author = {Ahmed, I and Ansari, YA and Parveen, G and Shukla, K and Bhise, M and Singh, S and Shaikh, UP and Ahmed, R and Ansari, I and Kumar, A},
title = {Neuroprotective Phytochemicals Targeting Amyloid and Tau Pathologies.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266446356260226085409},
pmid = {42220141},
issn = {1873-4294},
abstract = {The prevalence of Alzheimer's disease stands at more than 55 million individuals in the world, with estimates showing that the figure will increase to 152 million in 2050. Existing treatment methods are mostly symptomatic and do not address the underlying molecular disruptions, such as oxidative stress, mitochondrial dysfunction, and neuroinflammation. Neurodegeneration mediated by convergent pathways of these processes occurs through Aβ and hyperphosphorylated Tau. This is an overall review summarizing evidence from the PubMed, Scopus, and Web of Science databases as of 2025 on phytochemicals that can address both amyloid and tau pathologies simultaneously. This study presents a comprehensive assessment of more than 100 bioactive compounds across 7 chemical families with dual anti-amyloid and anti-tau effects, without prior reviews that address separate pathological targets or isolated classes of compounds with bioactivity. Major phytochemicals, such as curcumin, resveratrol, and epigallocatechin-3- gallate, suppress the activity of the beta-secretase, prevent the formation of amyloid fibrils, inhibit glycogen synthase kinase-3beta-mediated tau phosphorylation, and promote autophagy-lysosomal clearance. These molecules regulate NF-erythroid-2-related factor 2 signaling to inhibit reactive oxygen species and inhibit NF-κB-mediated neuroinflammation. Preclinical models show reductions in cognitive and neuropathological burden, but bioavailability and blood-brain barrier penetration pose barriers to clinical translation. Developed nanotechnology-based systems of delivery and structural modifications have potential in overcoming pharmacokinetic constraints. This represents a multi-target candidate therapy, a paradigm shift from the single-pathway therapeutics of the past, which may provide disease-modifying strategies beyond symptom management of Alzheimer's disease.},
}

@article {pmid42220203,
year = {2026},
author = {Eyre, B and Bonney, SK},
title = {EXPRESS: A perivascular perspective on the immune impacts in cerebral amyloid angiopathy.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261454165},
doi = {10.1177/0271678X261454165},
pmid = {42220203},
issn = {1559-7016},
abstract = {Cerebral amyloid angiopathy (CAA) is one of the most common small vessel diseases. With the deposition of amyloid beta within the walls of cerebral blood vessels, CAA can result in damage to blood vessels over time and ultimately intracerebral haemorrhage (ICH). Not only is CAA a leading cause of ICH but CAA is commonly observed in Alzheimer's disease (AD), yet there are still no effective treatments for CAA. The pathophysiology of CAA has yet to be fully elucidated but we know the perivascular environment is heavily impacted by the deposition of amyloid within blood vessels. In recent years, there has been an increased interest in the role that perivascular clearance may play in the development of the disease. Additionally, the role of the immune system has also come into question, especially regarding CAA-related inflammation. In this review, we aim to discuss the immune impacts of CAA within the perivascular environment, and probe how specific cells within this environment may be involved in the pathogenesis of CAA. Importantly, we also consider how some of these immune cells may be key treatment avenues to explore.},
}

@article {pmid42220275,
year = {2026},
author = {Ou, J and Hou, K and Fu, Y and Luo, Y and Yu, Q and Shen, M and Jiang, S and Zhu, J and Wang, Y and Lin, K and Lin, Z and Fang, M},
title = {EXPRESS: Brain Microvascular Endothelial Cells: Beyond a Barrier.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261454263},
doi = {10.1177/0271678X261454263},
pmid = {42220275},
issn = {1559-7016},
abstract = {The blood-brain barrier (BBB) has long been regarded as a passive, protective filter for the brain. This review re-evaluates the role of brain microvascular endothelial cells (BMECs)-from viewing them as static structural components to recognizing them as dynamic immunoregulatory sentinels within the neurovascular unit. BMECs actively sense inflammatory and pathogenic signals through pattern recognition receptors, integrate competing pathways such as Wnt/β-catenin and NF-κB, and make context-dependent decisions to balance barrier integrity with immune defense. In response to activation, they orchestrate neuroimmune communication by secreting chemokines, modulating adhesion molecules, and facilitating immune cell trafficking. Dysregulation of these functions contributes to the pathogenesis of various central nervous system disorders, including stroke, Alzheimer's disease, and multiple sclerosis, where BMECs dysfunction drives neuroinflammation and barrier breakdown. Further progress is required to resolve endothelial heterogeneity, develop precise tools for barrier function assessment, and define targeted interventions that modulate the immunoregulatory functions of BMECs in order to explain the mechanistic heterogeneity observed in neurological disorders. These efforts will deepen our understanding of the BBB's role in physiology and pathology, offering new strategies for the prevention and treatment of neurological diseases, and highlight BMECs as active participants in brain immunity and potential therapeutic targets.},
}

@article {pmid42221048,
year = {2026},
author = {Han, Y and Zhou, C and Wang, P and Karako, K and Song, P},
title = {The skin as a sentinel organ for neurodegeneration: An underrecognized target for dementia prevention.},
journal = {Intractable & rare diseases research},
volume = {15},
number = {2},
pages = {156-165},
pmid = {42221048},
issn = {2186-3644},
abstract = {Dementia prevention increasingly requires attention to modifiable systemic inflammatory stressors. In older adults, bullous pemphigoid (BP), herpes zoster (HZ), psoriasis, atopic dermatitis (AD), rosacea, prurigo nodularis (PN), and chronic pruritus are not merely disorders limited to the skin; they may signal or amplify neuroimmune vulnerability. Observational studies link BP with dementia and Alzheimer's disease, HZ with incident dementia and vascular cognitive injury, and psoriasis, AD, rosacea, or PN with smaller but biologically plausible cognitive risks. The proposed skin-brain axis integrates cytokine spillover, endothelial activation, blood-brain barrier dysfunction, BP180/ BP230 autoantigen sharing, varicellazoster virus neurotropism and vasculopathy, barrier failure, dysbiosis, itching-induced fragmented sleep, and medication or frailty-related cognitive toxicity. Clinically, cognitive impairment also worsens skin surveillance, hygiene, topical adherence, and recognition of pain, itching, infection, or blistering. Although causality and dementia prevention remain unproven, the evidence justifies proactive dermatological care in older adults and greater cognitive vigilance in older patients with severe inflammatory or pruritic dermatoses. Recombinant zoster vaccination, prompt antiviral therapy, steroid-sparing BP strategies, modern anti-inflammatory treatment for AD, psoriasis, and PN, and systematic attention to sleep, itching, caregiver capacity, and the medication burden are practical, low-regret steps while prospective brain-relevant trials are developed. This translational framework highlights mechanisms clinicians can now interrupt and endpoints investigators can soon measure. We propose that the skin should be recognized as a sentinel organ for neurodegeneration and that dermatological disease represents a potentially modifiable contributor to cognitive decline.},
}

@article {pmid42212431,
year = {2026},
author = {Kim, JP and Lee, H and Kim, BH and Kang, H and Shin, D and Yim, S and Kim, S and Seo, SW and Kim, HN},
title = {Genetically prioritized druggable targets for amyloid-β pathology highlight ACE as a therapeutic candidate in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261454540},
doi = {10.1177/13872877261454540},
pmid = {42212431},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by a neuropathological cascade that begins with amyloid-β (Aβ) deposition. The recent success of disease-modifying drugs targeting Aβ has demonstrated that modulating amyloidopathy can yield clinical benefits, underscoring the need for additional drugs affecting amyloid pathology.ObjectiveTo identify novel drug targets associated with Aβ accumulation in AD using Mendelian randomization (MR) analysis of the druggable genome.MethodsWe performed MR analysis on expression quantitative trait loci (eQTLs) of the druggable genome in relation to Aβ accumulation using summary-data-based MR (SMR). Blood eQTL data were obtained from the eQTLGen consortium, and brain eQTL data from BrainMeta and PsychENCODE, while Aβ positron emission tomography (PET) genome-wide association study data were derived from 11,816 non-Hispanic White participants across 13 cohorts. Co-localization analysis was conducted to enhance the reliability of the MR results, and additional validation was performed using blood and brain protein quantitative trait loci (pQTLs) as instrumental variables.ResultsThe SMR and co-localization analyses revealed causal associations between the druggable genome and Aβ accumulation, with APH1B identified in blood eQTL data and ACE, APH1B, and CR1 identified in brain eQTL data. Further analysis using pQTL data confirmed causal associations for ACE and CR1, with ACE showing a negative association with Aβ PET uptake.ConclusionsThese findings highlight potential target genes for AD treatment, and the protective effect of ACE against amyloid pathology suggests that alternative medications to ACE inhibitors may be preferred for blood pressure management in the context of AD. Overall, our study demonstrates the potential of MR to facilitate drug repurposing for AD.},
}

@article {pmid42213912,
year = {2026},
author = {Wilson, S and Beswick, E and Popp, Z and Rahman, S and Bhogal, S and Whitfield, T and Low, S and Khan, R and Tolley, C and Walker, Z and Au, R and Slight, SP},
title = {Acceptability of Technologies to Support Early Dementia Detection: Qualitative Study With the Boston University Alzheimer's Disease Center Cohort.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e84004},
pmid = {42213912},
issn = {1438-8871},
mesh = {Humans ; Aged ; Female ; *Dementia/diagnosis ; Male ; Boston ; *Alzheimer Disease/diagnosis ; Digital Health ; Cognitive Dysfunction/diagnosis ; Cohort Studies ; Aged, 80 and over ; Early Diagnosis ; Qualitative Research ; *Patient Acceptance of Health Care ; },
abstract = {BACKGROUND: Dementia is on the rise globally due to increasing life expectancies and population growth. Digital technologies may help detect early signs, enabling timely interventions to slow or reverse cognitive decline. However, to support the successful implementation of these digital technologies into health care settings, they must be acceptable to target users. Older adults and those with mild cognitive impairment (MCI) are at risk of developing dementia in later life and need to be able to use these technologies in order for this intervention to be approved and implemented in clinical practice.

OBJECTIVE: This study explored the perspectives of older adults and those living with a clinical diagnosis of MCI on the acceptability of using various digital technologies that have the potential to support early dementia detection.

METHODS: Participants were recruited from Boston University's Alzheimer's Disease Research Center. Participants selected at least 2 technologies from 9 different wearables and software to use for 2 weeks, at 3-month intervals, over a total duration of 2 years. A subgroup of self-selecting participants was interviewed after the first 2 weeks of use to gather initial perspectives regarding the acceptability of using the digital technologies. An inductive framework thematic analysis approach was used, assisted by NVivo (version 14.23.2; QSR International).

RESULTS: In total, 13 individuals living with a clinical diagnosis of MCI and 11 adults aged 65 years and older were interviewed. Our analysis identified five key themes: (1) gamification, (2) wearability, (3) user guidance, (4) burden of use, and (5) usefulness. Gamified apps were generally liked, although users with little experience of digital games needed time to adjust. Wearables resembling everyday accessories (eg, watches) were preferred, but complaints about tight or uncomfortable straps were frequently reported. Clear instructions were critical to support correct use, but many participants would have liked more troubleshooting support when technical issues arose. The use of 5 or more devices led to a high burden, especially when devices had practicality issues such as not being waterproof. Devices offering personal feedback were perceived as useful to satisfy personal interests, though some questioned their usefulness within health care. Participants raised concerns about losing valued personal interactions with health care professionals and questioned how their existing health conditions and treatment for such conditions may affect the validity of the data collected by the devices.

CONCLUSIONS: These findings can guide researchers in choosing appropriate devices and minimizing burden. Future work should explore the views of those experiencing digital exclusion to ensure equitable access to dementia-detection technologies.},
}

Humans
Aged
Female
*Dementia/diagnosis
Male
Boston
*Alzheimer Disease/diagnosis
Digital Health
Cognitive Dysfunction/diagnosis
Cohort Studies
Aged, 80 and over
Early Diagnosis
Qualitative Research
*Patient Acceptance of Health Care

@article {pmid42214568,
year = {2026},
author = {Zhong, RF and Chen, ZQ and Li, SF and Jiang, JG},
title = {Neuroprotective effects of Uncaria rhynchophylla alkaloid extracts against amyloid-β toxicity via regulation of oxidative stress pathways.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121918},
doi = {10.1016/j.jep.2026.121918},
pmid = {42214568},
issn = {1872-7573},
abstract = {Uncaria rhynchophylla is a important medicinal plant in Chinese traditional medicine for the treatment of neurological disorders, its alkaloid-rich constituents are considered the primary bioactive components responsible for its effects on the central nervous system.

AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of U. rhynchophylla alkaloid extract (URAs) against amyloid-β (Aβ)-induced neurotoxicity and oxidative stress, and elucidate underlying molecular mechanisms.

MATERIALS AND METHODS: URAs was prepared and characterized by LC-MS/MS for chemical profiling. The neuroprotective effects were evaluated using transgenic C. elegans CL2006 and CL2355, and H2O2-induced PC12 cells. In C. elegans, paralysis assay, Aβ deposition, and chemotaxis behavior were assessed. Oxidative stress markers including reactive oxygen species (ROS), lipofuscin accumulation, lipid peroxidation (MDA), and antioxidant enzyme activities (SOD, CAT) were measured. Quantitative real-time PCR was performed to examine the expression of genes of related signaling pathways. In PC12 cells, cell viability, ATP levels, and oxidative stress were evaluated.

RESULTS: URAs treatment significantly delayed Aβ-induced paralysis, reduced Aβ deposition, and improved chemotaxis behavior in transgenic C. elegans, while decreasing ROS, lipofuscin, and MDA, and increasing SOD and CAT activities. Furthermore, URAs modulated the expression of genes involved in Aβ metabolism, proteasome function, and antioxidant defense, and significantly suppressed the expression of p38 MAPK signaling pathway components.

CONCLUSION: Our findings demonstrate that URAs exert neuroprotective effects against Aβ toxicity and oxidative stress through multi-target mechanisms involving enhanced antioxidant defense, regulated proteostasis, highlighting their therapeutic potential for AD intervention.},
}

@article {pmid42214747,
year = {2026},
author = {Long, X and Shen, R and Yang, Y and Xu, Y and Wang, Y and He, Y and Xie, Y and Xie, X and Gao, D and Pang, X and Du, L},
title = {Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115856},
doi = {10.1016/j.expneurol.2026.115856},
pmid = {42214747},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.},
}

@article {pmid42216035,
year = {2026},
author = {Ibrahim, KS and Albaker, A and Abd-Elrahman, KS and Ferguson, SSG},
title = {Blocking estrogen receptors restores surface mGluR5 but not downstream signaling in female APP/PS1 Mice.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01314-1},
pmid = {42216035},
issn = {1756-6606},
support = {195977/CAPMC/CIHR/Canada ; 148656/CAPMC/CIHR/Canada ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) regulation of autophagy and accelerates disease progression in male AD mouse models. Yet, mGluR5 contribution to Aβ pathology is not observed in female AD mice, suggesting a distinct sex-selective profile. Given that estrogen receptors (ERs) form functional complexes with mGluR5 selectively in females, we assessed the role of ER activity in mGluR5 expression and downstream signaling in APPswe/PS1ΔE9 (APP/PS1) mice. We report here that mGluR5 cell surface expression is elevated in male but reduced in female APP/PS1 cortex relative to sex-matched wildtype controls, with total receptor expression remaining unchanged in both sexes. Treatment with the ER blocker, ICI 182,780, restored mGluR5 cell surface expression in female APP/PS1 mice but failed to rescue GSK3β and ULK1-regulated autophagy signaling. These findings indicate that male and female mGluR5 are embedded within intrinsically distinct signaling interactomes that are independent of ER regulation.},
}

@article {pmid41963989,
year = {2026},
author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC},
title = {Continuum of Core 1 biomarkers in preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41963989},
issn = {1758-9193},
support = {K99AG071837/NH/NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; K99AG071837/NH/NIH HHS/United States ; AARFD-21-849349/ALZ/Alzheimer's Association/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Biological Staging for Alzheimer’s disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma p-tau217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predict progression of downstream biomarkers and cognition.

METHODS: We used baseline plasma p-tau217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether p-tau217 and amyloid-PET burden within this group were associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage.

RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, baseline plasma p-tau217 and amyloid-PET burden were associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean [SD] follow-up time for tau-PET: 4.2 [2.1] years and MRI: 4.2 [1.9] years), as well as faster cognitive decline (mean [SD] follow-up time for PACC: 5.7 [1.6] years) (all p < 0.05). Plasma p-tau217 and amyloid-PET burden were also associated with higher risk of progression to Biological Stage B+.

DISCUSSION: In CU individuals in the initial stage of AD (Biological Stage A), early changing AD biomarkers provide prognostic information of downstream markers of disease. Evaluation of the utility of these measures in a real-world setting is warranted.

TRIAL REGISTRATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2013. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02044-1.},
}

@article {pmid42001005,
year = {2026},
author = {Bayar, E and Cengiz, T and Erdoğan, F and Coşkun, HS and Tomak, Y},
title = {Impact of comorbidities on preoperative and postoperative outcomes in hip fracture patients.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42001005},
issn = {1471-2318},
abstract = {BACKGROUND: Hip fractures represent a major public health concern due to their increasing incidence in the aging population and their association with significant morbidity and mortality. Comorbidities are known to complicate both the surgical management and rehabilitation process, yet their specific impact on outcomes remains variable across studies.

OBJECTIVE: This study aimed to determine the prevalence and distribution of comorbidities in patients who presented with hip fractures and underwent surgical treatment, to evaluate perioperative and postoperative risk factors retrospectively, and to compare these findings with the existing literature.

METHODS: A retrospective descriptive analysis was conducted on 589 patients aged ≥ 60 years who were surgically treated for hip fractures between 2013 and 2024 at a tertiary university hospital. Demographic characteristics, surgical protocols, anesthesia types, revision rates, infection, dislocation, mobilization outcomes, hospital stay, intensive care admissions, and mortality were systematically analyzed in relation to comorbidity profiles and the number of comorbidities. Statistical analyses included chi-square, Fisher’s exact test, Mann-Whitney U, and Kruskal-Wallis tests, with p < 0.05 considered significant.

RESULTS: Hypertension (59.1%), diabetes mellitus (33.6%), coronary artery disease (21.4%), and Alzheimer’s disease (21.4%) were the most frequent comorbidities. Revision surgery was significantly associated with diabetes mellitus and congestive heart failure. Diabetes mellitus, coronary artery disease, and chronic renal failure were strong predictors of postoperative infection. While the mean hospital stay was significantly prolonged in patients with ≥ 3 comorbidities, mortality was significantly associated only with oncological diseases and chronic renal failure. Contrary to expectations, no significant association was found between overall mortality and the number of comorbidities.

CONCLUSION: Comorbidities, particularly diabetes mellitus, congestive heart failure, oncological diseases, and chronic renal failure, substantially influence surgical outcomes, postoperative complications, and hospitalization in hip fracture patients. However, the number of comorbidities alone was not a predictor of mortality, highlighting the importance of the type rather than the quantity of comorbid conditions. These findings underscore the need for individualized perioperative planning and comprehensive patient counseling to reduce risks and improve postoperative outcomes.},
}

@article {pmid42210804,
year = {2026},
author = {Devanand, DP and Huey, ED and Qian, M and Wei, R and Motter, JN and Nedic, L and Andrews, HF and Deliyannides, DA and Maayan, L and Graff, J and Deehan, E and Acosta, EP and Zanderigo, F and Goldberg, TE},
title = {Valacyclovir Treatment in Mild Cognitive Impairment: The VALMCI Randomized Clinical Trial.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000735},
pmid = {42210804},
issn = {1546-4156},
abstract = {BACKGROUND: Evidence from neuroscience, epidemiology, and electronic health records studies implicates herpes simplex viruses (HSV) as potentially etiologic for Alzheimer disease (AD).

METHODS: The VALMCI study was conducted in a research outpatient clinic specializing in memory disorders. The efficacy and side effects of valacyclovir 4 g/day were compared with placebo in a 12-month pilot, randomized, double-blind trial of participants with mild cognitive impairment (MCI), seropositivity to HSV1 or HSV2, and positive 18F-florbetapir PET scan.

RESULTS: Totally, 42 of 50 participants (84%) completed the trial. In linear mixed-effects model analyses with age, sex, and apolipoprotein E e4 genotype as covariates, change in the primary outcome of 18F-florbetapir PET mean SUVR was not significant with least-squares mean difference -0.01 (95% CI: -0.12 to 0.10; P=0.82). For secondary cognitive and functional outcomes, PACC composite z-score showed the least square mean difference 0.16 (95% CI: -0.17 to 0.49; P=0.32), and ADCS-ADL-PI score showed the least square mean difference 1.96 (95% CI: -0.43 to 4.34; P=0.11).

CONCLUSION: The results do not support the use of valacyclovir in the treatment of individuals with MCI with HSV seropositivity and PET amyloid positivity.},
}

@article {pmid42211120,
year = {2026},
author = {Song, H and Yang, M and Wu, S and Dai, Q and Qin, W and Xie, W and Chen, Y and Jiang, X and Zhang, X and Deng, X and Ouyang, C and Zhang, Y and Liu, X and Zhu, Y and Huang, G},
title = {Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116033},
pmid = {42211120},
issn = {2589-0042},
abstract = {Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata, has emerged as a promising treatment for Alzheimer's disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.},
}

@article {pmid41928225,
year = {2026},
author = {Kato, M and Isazawa, A and Ohki, A and Fujita, A and Araki, M and Yanaizu, M and Kino, Y},
title = {Functional sQTLs regulating PTK2B exon 31 splicing uncover an RNA-dependent modulation of its kinase activity and cellular phenotype.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {41928225},
issn = {1478-811X},
support = {19J15024//Ministry of Education, Culture, Sports, Science and Technology/ ; 19K07982//Ministry of Education, Culture, Sports, Science and Technology/ ; },
abstract = {BACKGROUND: Genome-wide association studies have shown that polymorphisms in PTK2B (Protein Tyrosine Kinase 2 Beta), encoding the calcium-sensitive tyrosine kinase PYK2 (Proline-rich tyrosine kinase 2), are associated with an increased risk of Alzheimer’s disease (AD). However, it remains unclear which genetic variants of PTK2B are functionally important. A recent transcriptome-wide association study has identified alternative splicing of exon 31 in PTK2B as being associated with AD, and proposed rs2251430 as the relevant splicing quantitative trait locus (sQTL). Here, we aimed to elucidate the regulatory mechanisms and functional significance of exon 31 splicing.

METHODS: Alternative splicing of exon 31 was evaluated using publicly available RNA-seq data. To investigate the regulation of exon 31 splicing, we performed RT-PCR, RNA pull-down assays, Liquid Chromatography–Tandem Mass Spectrometry, and RNA immunoprecipitation. Western blotting, immunofluorescence, and co-immunoprecipitation analyses were conducted to examine the effects of exon 31 and its polymorphisms on PYK2 protein expression and function. The impact of exon 31 on cellular phenotypes was further assessed using antisense oligonucleotide (ASO) treatment in HeLa and HMC3 cells.

RESULTS: We detected exon 31 skipping in certain human cell types, but not in mice, and observed its increase in microglia during AD progression. We then identified rs751019 and rs751018, both located near rs2251430, as sQTLs that affect exon 31 splicing, with rs751019 having a greater impact. Among RNA-binding proteins that interact with the surrounding sequence of rs751019, PCBP1 and PCBP2 were found to redundantly regulate exon 31 inclusion. PYK2 lacking exon 31 exhibited reduced protein expression and kinase activity, which in turn resulted in diminished phosphorylation of its substrate, GSK3β, with little change in calmodulin binding and intracellular localization. Moreover, ASO-induced exon 31 skipping decreased cell migration in a wound healing assay. It also increased multinucleation in human microglia-like HMC3 cells, a process recently identified in protective microglia.

CONCLUSIONS: Our study validates rs751019 and rs751018 as functional sQTLs that influence PTK2B exon 31 splicing. It also identifies species-specific alternative splicing of exon 31 as a modulator of PYK2 expression and kinase activity, thereby linking sQTL-associated genetic variants to molecular and cellular changes that may underlie AD pathogenesis.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02835-x.},
}

@article {pmid42167701,
year = {2026},
author = {Hou, P and Li, X and Yan, Y and Lu, Q and Wang, J and Yuan, M and Wang, X and Wang, X},
title = {Polyethylene terephthalate microplastics activate AKT1 signaling and induce neurotoxic responses in SH-SY5Y cells.},
journal = {Toxicology and applied pharmacology},
volume = {513},
number = {},
pages = {117873},
doi = {10.1016/j.taap.2026.117873},
pmid = {42167701},
issn = {1096-0333},
abstract = {Microplastic exposure has emerged as a growing environmental health concern, with increasing evidence suggesting potential effects on the nervous system. However, the molecular basis by which polyethylene terephthalate (PET) contributes to Alzheimer's disease (AD)-related neurotoxicity remains unclear. This study examined whether PET induces neuronal injury by activating the AKT1 signaling pathway. Network toxicology integrating PubChem, STITCH, SwissTargetPrediction, OMIM, TTD, and GeneCards was used to identify PET-associated targets relevant to AD. Core targets were analyzed with Cytoscape, followed by GO and KEGG enrichment using R and clusterProfiler. Molecular docking and molecular dynamics simulations characterized the interaction between PET and AKT1. For in vitro validation, SH-SY5Y cells were treated with 100 μg/mL PET for 24 h or 48 h to detect cytotoxicity and molecular alterations. Four experimental groups were set in this study: Control, PET, PET + MK2206 (1 μM) and MK2206 (1 μM) single treatment groups. PET exposure reduced cell viability, increased intracellular reactive oxygen species (ROS) levels, and enhanced AKT phosphorylation at Ser473, while MK2206 attenuated these effects. These research results show that PET microplastics can induce neurotoxic reactions by activating the AKT1 pathway.},
}

@article {pmid42201342,
year = {2026},
author = {Aydın, Ş and Dalkılınç, E and Özdemir, S and Küçükler, S and Çomaklı, S and Adıgüzel, A},
title = {Neuroprotective effects of luteolin against aluminum-induced brain injury via chelation and antioxidant pathways.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42201342},
issn = {1432-1912},
abstract = {Aluminum (Al) is a widespread environmental neurotoxin linked to several neurodegenerative conditions through oxidative stress, inflammation, and apoptosis. Because it is present in food, water, pharmaceuticals, and consumer products, chronic exposure is nearly unavoidable and poses a public health concern. Luteolin (LUT), a natural flavone with antioxidant, anti-inflammatory, and metal-chelating properties, has emerged as a potential neuroprotective agent. This study investigated the protective effects of LUT against aluminum chloride (AlCl3)-induced neurotoxicity in rats. Sprague-Dawley rats received AlCl3 (4.2 mg/kg, i.p.) alone or together with LUT (25 or 50 mg/kg, p.o.) for 30 days. Behavioral performance was evaluated using novel object recognition and open-field tests. ICP-MS was employed to quantify brain Al levels, and complementary analyses were conducted to assess oxidative stress, neuroinflammation, apoptosis-related gene expression, neuroplasticity markers (BDNF, c-Fos), and cholinergic function (AChE). AlCl3 exposure significantly increased brain Al accumulation and induced oxidative stress, inflammation, apoptosis, and behavioral deficits. Although LUT co-treatment led to an apparent increase in total brain Al, this rise is likely attributable to the formation of Al-LUT complexes. This interpretation is supported by the marked reduction in Al-induced oxidative stress, apoptosis, and inflammation, accompanied by improved behavioral outcomes. This evaluation reveals that LUT provides protection in an environmental Al neurotoxicity model, offering insights beyond classical Alzheimer's disease contexts. Although its antioxidant and anti-inflammatory effects are well documented, evidence for its efficacy against environmentally induced Al neurotoxicity is still lacking.},
}

@article {pmid42202469,
year = {2026},
author = {Jessen, F and Dell'Agnello, G and Zimmer, JA and Sapin, C and Dichter, S and Doty, E and Epelbaum, S and Evans, CD and Hauck, PM and Khanna, R and Brooks, DA and Sims, JR and Agosta, F and , },
title = {Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100605},
doi = {10.1016/j.tjpad.2026.100605},
pmid = {42202469},
issn = {2426-0266},
abstract = {BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer's disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.

OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.

METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.

RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.

CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.},
}

@article {pmid42202980,
year = {2026},
author = {Sánchez-Valle, R and Alcolea, D and Ferrer, GA and Balasa, M and Naranjo, IC and Fortea, J and Lladó, A and Lleó, A and Montes, AM and Lozano, LM and Martínez-Lage, P and Matias-Guiu, JA and Mendioroz, M and Martinez, DAP and Ripoll, GP and Riverol, M and Sanchez-Juan, P and Bondía, HV and , },
title = {Appropriate use recommendations of the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group on anti-amyloid antibodies in the treatment of Alzheimer disease.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502075},
doi = {10.1016/j.nrleng.2026.502075},
pmid = {42202980},
issn = {2173-5808},
abstract = {INTRODUCTION: Two anti-amyloid monoclonal antibodies (mAb) have recently been approved by the European Commission for the treatment of Alzheimer disease (AD). In this context, the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides recommendations on practical aspects of the use of these drugs in Spain, which are intended to complement the indications described by regulators.

DEVELOPMENT: Fifty-seven members of the study group participated in the consensus process (January-September 2025), which includes recommendations on criteria for selecting candidates, adverse reactions, monitoring, criteria for suspension of treatment, shared physician-patient decision-making, and requirements of prescribing centres. All participants were invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments.

CONCLUSIONS: The introduction of the first anti-amyloid mAb represents a paradigm shift in the management of AD, but is not free of challenges. The participating experts showed a high level of consensus on basic clinical and practical considerations, with the requirements of prescribing centres and criteria for treatment suspension being the areas that generated the most debate. Participants noted concerns about equity of access and implementation into current care, particularly if insufficient resources are allocated to this implementation. This document will require updates in line with new knowledge and/or approval of new drugs in this class.},
}

@article {pmid42203570,
year = {2026},
author = {Ho, NCW and Zhukovsky, P and Rajji, TK and Bowie, CR and Brooks, H and Butters, MA and Chen, Y and Fischer, CE and Flint, AJ and Herrmann, N and Lanctôt, KL and Lee, A and Mah, L and Marawi, T and Pollock, BG and Ryan, JD and Schoer, N and Ma, C and Voineskos, AN and Mulsant, BH and , },
title = {Brain Structures and Cognitive Decline: Moderation Analysis of the PACt-MD Randomized Clinical Trial of Brain Stimulation Plus Cognitive Remediation in Older Adults With Remitted Depression or Mild Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.04.008},
pmid = {42203570},
issn = {1545-7214},
abstract = {OBJECTIVE: To identify which patients with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI) benefit from cognitive remediation (CR) plus transcranial direct current stimulation (tDCS).

DESIGN: We conducted a moderator analysis to examine the effects of baseline brain magnetic resonance imaging (MRI) measures on the impact of CR + tDCS on cognitive decline in Prevention of Alzheimer's dementia with CR plus tDCS in MCI and Depression (PACt-MD), a double-masked randomized two-arm controlled trial with assessments at baseline, two months, and yearly for three to seven years.

SETTING: Five academic hospitals in Toronto, Canada.

PARTICIPANTS: A total of 246 participants with rMDD, MCI, or both, with an analyzable baseline MRI.

INTERVENTION: CR + tDCS or sham CR + sham tDCS.

MEASUREMENTS: Overall cortical thickness, overall fractional anisotropy, and cortical thickness in an a-priori composite region of interest (ROI); changes in global cognition, executive function, or verbal memory.

RESULTS: Overall cortical thickness moderated decline in global cognition (Χ² = 10.43, df = 3, p = 0.015); ROI cortical thickness moderated treatment-related changes in global cognition (Χ² = 29.05, df = 3, p <0.001), executive function (Χ² = 11.57, df = 3, p = 0.009), and verbal memory (Χ² = 16.08, df = 3, p = 0.001).

CONCLUSION: Future work needs to confirm that cortical thickness can be used to select adults at risk for dementia who are the most likely to benefit from CR + tDCS. CLINCIALTRIALS.

GOV IDENTIFIER: NCT02386670.},
}

@article {pmid42204876,
year = {2026},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable markers for early cognitive decline: Plasma p-tau217, subjective cognitive concerns, and digital testing: Results from the A4/LEARN studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71505},
doi = {10.1002/alz.71505},
pmid = {42204876},
issn = {1552-5279},
support = {//public-private philanthropic partnership/ ; //National Institutes of Health/National Institute on Aging/ ; //Eli Lilly and Company/ ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Avid and Cogstate/ ; },
mesh = {Humans ; Aged ; *Cognitive Dysfunction/diagnosis/blood ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; *Alzheimer Disease/blood ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers confirm Alzheimer's disease (AD) pathology but are impractical for large-scale screening. Plasma phosphorylated tau at threonine 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We assessed their separate and combined predictive value for cognitive decline.

METHODS: We analyzed 1064 cognitively unimpaired adults (ages 65-85 years) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4; amyloid-positive) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN; amyloid-negative) studies. Baseline assessments included apolipoprotein E (APOE) ε4 status, hippocampal volume, amyloid PET, plasma p-tau217, Cognitive Function Index (CFI), and Cogstate Computerized Battery (CCB). Cognitive impairment was defined as conversion from a Clinical Dementia Rating Global Score (CDR-GS) of 0 to ≥0.5 over 240 weeks.

RESULTS: During the follow-up, 34.1% developed cognitive impairment. Higher p-tau217, higher CFI, and lower CCB were associated with higher odds of converting to CDR-GS >0 across all cohorts.

DISCUSSION: P-tau217, CFI, and CCB each independently predict cognitive decline, offering practical, non-invasive tools for early AD risk stratification and trial enrichment.},
}

Humans
Aged
*Cognitive Dysfunction/diagnosis/blood
*tau Proteins/blood
Biomarkers/blood
Female
Male
Aged, 80 and over
Neuropsychological Tests
Positron-Emission Tomography
*Alzheimer Disease/blood
Longitudinal Studies

@article {pmid42206050,
year = {2026},
author = {Deng, HX and Cao, JL and Wu, Y and Jiang, SJ and Fang, QQ and Zhu, BY and Jiang, YJ},
title = {AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1814357},
pmid = {42206050},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; *Immunity, Innate ; *Protein Folding ; Animals ; *Artificial Intelligence ; *Proteostasis Deficiencies/immunology ; },
abstract = {Neurodegenerative diseases encompass a diverse group of disorders ranging from adult-onset conditions such as Alzheimer's and Parkinson's disease to pediatric forms including neuronal ceroid lipofuscinoses (NCLs), Niemann-Pick type C (NPC), and infantile neuroaxonal dystrophy (INAD), all of which are characterized by protein misfolding and chronic neuroinflammation. During their occurrence and development, the innate immune system, especially the immune responses mediated by microglia in the central nervous system, plays a crucial regulatory role. Increasing evidence indicates that misfolded and abnormally aggregated proteins, such as β-amyloid (Aβ), Tau, α-synuclein, and TDP-43, are not only neurotoxic factors but can also act as damage-associated molecular patterns (DAMPs) recognized by innate immune receptors, thereby triggering persistent neuroinflammatory responses. However, traditional experimental and computational methods still have significant limitations in systematically analyzing the "protein misfolding-innate immune activation" mechanism. In recent years, artificial intelligence has made breakthrough progress in protein structure prediction, multi-conformation modeling, and integration of multi-omics data, providing a new research paradigm for revealing the intrinsic relationship between protein misfolding and innate immunity across the spectrum of neurodegenerative diseases. This article systematically reviews the latest applications of artificial intelligence in predicting the conformational characteristics of misfolded proteins, simulating the protein aggregation process, revealing the mechanism of innate immune perception, and reconstructing the regulatory network of neuroinflammation. It focuses on discussing the significance of deep learning models such as AlphaFold, I-TASSER, RoseTTAFold, Phyre2, and ESMFold in the field of protein structure prediction, as well as the related research on multi-modal AI technology in revealing the complex molecular mechanisms behind neurodegenerative diseases, such as combining AI with mathematical models to simulate the spread of misfolded proteins and further exploring the association with disease progression. The review also highlights the potential of AI to address the diagnostic challenges unique to pediatric neurodegenerative disorders, which, despite their rarity, collectively impose devastating lifelong burdens. In summary, AI tools not only deepen our understanding of the molecular mechanisms underlying both adult and childhood neurodegenerative diseases but also open up new avenues for developing innovative diagnostic tools and treatment methods.},
}

Humans
*Neurodegenerative Diseases/immunology/metabolism
*Immunity, Innate
*Protein Folding
Animals
*Artificial Intelligence
*Proteostasis Deficiencies/immunology

@article {pmid42207225,
year = {2026},
author = {Ed-Day, S and Kacimi, FE and El Gui, R and Didou, L and Ibouzine-Dine, L and El Kourchi, C and Boulbaroud, S and Haddan, A and Harhar, H and Azzaoui, FZ},
title = {Erythrina caffra extract restores memory, modulates cholinergic dysfunction, neuroinflammation, and attenuates oxidative stress in cadmium-induced alzheimer's disease-like pathology in rats.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42207225},
issn = {1573-4978},
mesh = {Animals ; Oxidative Stress/drug effects ; *Plant Extracts/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Rats, Wistar ; Cadmium/toxicity ; Male ; *Erythrina/chemistry/metabolism ; *Memory/drug effects ; Antioxidants/pharmacology ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Acetylcholine/metabolism ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: Cadmium (Cd) is a well-established neurotoxic heavy metal. Several epidemiological studies have highlighted its involvement in the pathogenesis of Alzheimer's disease (AD). AD is a multifactorial disorder influenced by environmental factors such as heavy metals. Erythrina caffra (E. caffra) is a medicinal plant rich in bioactive compounds with anti-inflammatory, antioxidant, and anticholinesterase properties. However, its protective potential against Cd-induced neurodegeneration remains insufficiently explored. This study investigated the effects of Cd on memory, cholinergic function, oxidative stress, and neuroinflammation, as key AD-related pathophysiological features, and evaluated the therapeutic potential of E. caffra seeds ethanolic extract.

METHODS AND RESULTS: AD-like alterations were induced in Wistar rats by intracerebroventricular (ICV) administration of cadmium chloride (CdCl2). Animals were treated with E. caffra ethanolic extract (2.5 mg/kg) or memantine (20 mg/kg) by oral gavage. Behavioral, neurobiochemical, and histological analyses were performed to assess memory, cholinergic function, oxidative stress, neuroinflammation, and neuronal integrity. Cd exposure significantly impaired memory and disrupted cholinergic function, as evidenced by reduced acetylcholine (ACh) levels in the hippocampus. Moreover, it induced oxidative stress, marked by decreased catalase (CAT), superoxide dismutase (SOD), and non-protein thiols (NPSH), alongside increased proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and hippocampal neuronal loss. Treatment with E. caffra and memantine significantly ameliorated these alterations.

CONCLUSIONS: E. caffra extract demonstrates neuroprotective effects against Cd-induced AD-like pathology by modulating oxidative stress, neuroinflammation, and cholinergic dysfunction. These findings suggest its potential as a promising therapeutic candidate for mitigating neurodegenerative processes associated with AD.},
}

Animals
Oxidative Stress/drug effects
*Plant Extracts/pharmacology
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Rats
Rats, Wistar
Cadmium/toxicity
Male
*Erythrina/chemistry/metabolism
*Memory/drug effects
Antioxidants/pharmacology
Hippocampus/drug effects/metabolism
Neuroinflammatory Diseases/drug therapy/metabolism
Disease Models, Animal
Acetylcholine/metabolism
Neuroprotective Agents/pharmacology

@article {pmid42207606,
year = {2026},
author = {Papamicaël, C and Gembus, V and Gourand, F and Levacher, V},
title = {Redox Heterocyclic Platforms Engineered for Brain Drug Delivery and Beyond.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e70162},
doi = {10.1002/tcr.70162},
pmid = {42207606},
issn = {1528-0691},
abstract = {Overcoming the blood-brain barrier remains one of the most formidable challenges in the diagnosis and treatment of central nervous system disorders. In this account, we showcase our contributions to the field of redox-responsive heterocycles, most notably 1,4-dihydroquinolines and 1,4-dihydropyridines, designed as powerful platforms for targeted brain delivery. Our work builds on the chemical delivery system and bioprecursor prodrug strategies pioneered by Bodor et al. We have focused on the development of redox-activated drug carriers and "bio-oxidizable" prodrugs, which enable efficient transport of neurotransmitters, neuropeptides, and radiotracers for advanced brain imaging, as well as cholinesterase and kinase inhibitors for the treatment of Alzheimer's disease. Last but not least, these versatile heterocyclic systems offer unprecedented perspectives in synthetic methodology, driving breakthrough advances in peptide synthesis and atroposelective amide bond construction.},
}

@article {pmid42207745,
year = {2026},
author = {Bhat, KMR and Lc, P and Thonse, NK and Potu, BK and Kateel, R},
title = {Neuroprotective Effects of Ginkgo biloba Extract in Neurological Disorders: Integrating Anti-Inflammatory and Antioxidant Mechanisms.},
journal = {Complementary medicine research},
volume = {},
number = {},
pages = {1-40},
doi = {10.1159/000552633},
pmid = {42207745},
issn = {2504-2106},
abstract = {BACKGROUND: Neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke are major causes of global disability and mortality. Neuroinflammation and oxidative stress play central roles in their pathogenesis. Ginkgo biloba extract (GBE), particularly the standardized formulation EGb 761, contains flavonoids and terpenoids that exert antioxidant, anti-inflammatory, and mitochondrial-protective effects. These pleiotropic actions position GBE as a promising candidate for neuroprotection.

SUMMARY: This narrative review synthesizes evidence from preclinical and clinical studies on the neuroprotective actions of GBE. Experimental data demonstrate that GBE attenuates oxidative stress by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses, while simultaneously downregulating pro-inflammatory mediators through NF-κB inhibition and NLRP3 inflammasome suppression. Additional benefits include stabilization of mitochondrial function, modulation of neurotransmission, and prevention of apoptosis. Preclinical models consistently show improvements in cognition, motor function, and neuronal survival across diverse disease contexts. Clinical findings, however, are mixed: some randomized trials report improved cognition and functional outcomes in dementia and Parkinsonism, whereas others show no superiority over placebo. Variability in study design, extract standardization, and treatment regimens contribute to these discrepancies.

KEY MESSAGES: GBE exerts multifaceted neuroprotective effects through combined antioxidant, anti-inflammatory, mitochondrial, and neurotransmitter-modulating actions. Preclinical evidence strongly supports its role in mitigating pathological processes underlying Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic injury. But clinical outcomes remain inconsistent. GBE holds potential as a safe, multi-target adjunctive therapy for complex central nervous system disorders, but translation into consistent clinical practice requires further validation.},
}

@article {pmid42208269,
year = {2026},
author = {Saxena, S and Kaur, J and Singh, TG and Kumar, M and Awasthi, A},
title = {Beyond the brain barrier: Hybrid nanoparticles orchestrating intelligent neuro-theranostics.},
journal = {Advances in colloid and interface science},
volume = {356},
number = {},
pages = {103954},
doi = {10.1016/j.cis.2026.103954},
pmid = {42208269},
issn = {1873-3727},
abstract = {Hybrid nanoparticles (HNPs) that integrate organic and inorganic components have been recognized as one of the most sophisticated solutions in the field of nanomedicine to surpass the physiological limitations of the blood-brain barrier (BBB). By the combination of biocompatibility, flexibility, and the capacity of functionalization of the organic shells with the magnetic, optical, or structural precision of the inorganic cores, HNPs provide receptor-mediated transport, controlled drug release, and multimodal imaging with high efficiency. This review details the molecular mechanisms of HNPs crossing the BBB, such as receptor-mediated, adsorptive, carrier-mediated, and biomimetic transcytosis, and also points to the role of the advanced conjugation chemistries like EDC/NHS coupling, thiol‑gold anchoring, click reactions, and redox-cleavable linkers in enhancing targeting fidelity. The therapeutic improvements in the major neurological diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease, and glioblastoma, are discussed with the help of figures, which illustrate enhanced bioavailability, gene silencing, mitochondrial targeting, and integrated photothermal or magnetic responsiveness. Moreover, the review discusses potential diagnostic applications such as multimodal MRI/PET/NIR-II imaging, molecular biosensing, and theranostic nanoplatforms, which link the real time visualization with the targeted treatment. To conclude, we point out the upcoming directions comprising biomimetic coatings, AI guided nanoparticle design, stimuli responsive logic-gated systems, and clinically scalable biodegradable hybrids. In sum, HNPs embody a radically different strategy to precision neuro-nanomedicine, thereby providing a seamless avenue for diagnosis, targeted therapy, and continuous disease monitoring within a single intelligent nanosystem.},
}

@article {pmid42208565,
year = {2026},
author = {Serrano-Pozo, A and Escott-Price, V and Grinberg, LT and Pascoal, T and Suárez-Calvet, M and Dubois, B and Sperling, RA},
title = {Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {407},
number = {10544},
pages = {2241-2262},
doi = {10.1016/S0140-6736(26)00198-4},
pmid = {42208565},
issn = {1474-547X},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control ; Biomarkers ; },
abstract = {Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting its progression. In this Seminar, we summarise this progress and highlight unmet needs and areas of research priority.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/epidemiology/prevention & control
Biomarkers

@article {pmid42210357,
year = {2026},
author = {Behzad, F and Leili, FR and Ebrahimi, MJ and Moafi, M and Kenari, PB and Alizadeh, A and Adeli, S and Khosravani, M and Jadidi Kouhbanani, MA and Fahanik-Babaei, J},
title = {Plant-mediated green nanoparticles: combining nanometal and biometabolite potential for Alzheimer's treatment.},
journal = {Biomedical engineering online},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12938-026-01572-z},
pmid = {42210357},
issn = {1475-925X},
abstract = {Alzheimer's disease (AD) can cause cognitive and memory dysfunction due to insufficient acetylcholine (ACh). In principle, acetylcholinesterase (AChE) hydrolyzes ACh into acetic acid and choline, rendering the latter inactive. Acetylcholinesterase inhibitors (AChEI) are currently the main treatment strategy used to increase ACh availability and decrease the effects of cholinergic loss. The FDA has currently approved donepezil, rivastigmine, and galantamine (GAL) as AchEI drugs to treat AD. Among these drugs, only the alkaloid galantamine is found naturally among the AChEIs. The synergistic effect of plant metabolites and metal nanoparticles (MNPs) presents a promising avenue for AD treatment. Green synthesis approach leverages the unique properties of MNPs combined with the therapeutic potential of plant-derived compounds. In the present review, recent developments in nanotechnology, including the green synthesis of MNPs, have been discussed in relation to the treatment of AD. Given the recent advancements, we hope that the combination of nanotechnology and medicinal plants will eventually result in the development of highly successful strategies for the treatment of AD.},
}

@article {pmid41963962,
year = {2026},
author = {Li, Y and Wu, H and Yang, J and Weedor, JG and Ding, H and Cui, W and Cui, B and He, Z and Zhang, W and Xing, Y and Zeng, F and Huang, X and Zheng, K and Shen, Y and Yu, Y and Pan, W and Yang, X},
title = {Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41963962},
issn = {1742-2094},
support = {Nos. 202310313083Y//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313020//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313017//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. JC20250007//the Faculty Development Grant of Basic Medical Sciences in Xuzhou Medical University/ ; Nos. 82372283//the National Natural Science Foundation of China/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; No. 2022M710120//China Postdoctoral Science Foundation/ ; },
abstract = {UNLABELLED: Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03761-y.},
}

@article {pmid42199923,
year = {2026},
author = {Putri, VA and Hapsari, RS and Amalia, R},
title = {L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {579603},
pmid = {42199923},
issn = {1176-6328},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive decline. Despite the widespread use of symptomatic treatments, including acetylcholinesterase inhibitors and dopaminergic agents, these disorders remain incurable and lack disease-modifying therapies. L-α-Glycerylphosphorylcholine (L-α-GPC), a naturally occurring choline-containing phospholipid, has attracted interest for its dual roles as a precursor to acetylcholine biosynthesis and a modulator of neuroprotective signaling pathways. This narrative review summarizes current preclinical and clinical evidence regarding the mechanistic and clinical relevance of L-α-GPC in neurodegenerative disorders associated with cognitive impairment. Preclinical studies suggest that L-α-GPC can cross the blood-brain barrier, enhance cholinergic neurotransmission, upregulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF), and modulate inflammatory responses, including those involving the α7 nicotinic acetylcholine receptor pathway. In animal models, L-α-GPC has been associated with improved cognitive performance, reduced neuroinflammation, and attenuation of amyloid-β and tau-related pathological features. Clinical studies have reported potential benefits of L-α-GPC, either as monotherapy or in combination with agents such as donepezil, in patients with AD, vascular dementia, mild cognitive impairment (MCI), and PD-related cognitive decline. However, the interpretation of these findings should be cautious because the available evidence remains heterogeneous, with notable variability in study design, dosage regimens, treatment duration, and outcome measures. Further well-designed, large-scale randomized controlled trials, together with biomarker-based assessments, are needed to clarify the therapeutic relevance and optimal clinical application of L-α-GPC in cognitive decline and neurodegenerative disorders. Overall, current evidence indicates that L-α-GPC may represent a promising adjunctive approach, although more robust validation is still required.},
}

@article {pmid42201167,
year = {2026},
author = {Bonny, G and Mahfooz, K and Garcia-Rates, S and Hasan, S and Greenfield, SA},
title = {Evaluating the Efficacy of Monoclonal Antibodies Against a Bioactive Peptide Involved in Alzheimer's Disease: A Methodological Approach.},
journal = {Methods and protocols},
volume = {9},
number = {3},
pages = {},
pmid = {42201167},
issn = {2409-9279},
abstract = {Antibody treatment for Alzheimer's disease is an evolving therapeutic strategy that ensures high affinity and specificity to the target antigen; however, current approaches have proven only partially successful. A 14-mer peptide, T14, is twice as high in Alzheimer's brains and has been identified as a primary driver in the neurodegenerative process. Previously, the polyclonal antibody Ab-19 was shown to be as effective as the T14 receptor blocker (NBP-14) in reducing the toxic calcium influx in PC12 cells. The aim of this study was to establish a thorough validation process in order to evaluate the efficacy of respective anti-T14 monoclonal antibodies in T14 detection and rescuing potential from T14-induced toxicity in PC12 cells. Subsequently, we assessed the binding affinity of the most promising antibody, THK-117, via quantitative indirect conjugated T14 ELISA assays. The level of efficacy shown proved to be comparable to the polyclonal antibody, yet with the additional advantage of robust manufacturing reproducibility and high binding specificity toward the T14 epitope. With a notably low EC50, THK-117 can be viewed as a promising candidate for humanization, offering a strong potential as a therapeutic monoclonal antibody for the treatment and prevention of Alzheimer's disease.},
}

@article {pmid41992240,
year = {2026},
author = {Bhargavan, B and Annadurai, N and Kanmogne, GD},
title = {Effects of HIV and azidothymidine on Alzheimer's-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity.},
journal = {Fluids and barriers of the CNS},
volume = {23},
number = {1},
pages = {},
pmid = {41992240},
issn = {2045-8118},
abstract = {BACKGROUND: Despite increased life expectancy with antiretroviral therapy, people with HIV (PWH) have significantly higher prevalence of comorbid diseases, including neurocognitive impairment. PWH and neurocognitive impairment often show features of Alzheimer’s-like pathologies, including increased brain amyloid-beta (Aβ) and phospho-Tau; it is not known if antiretroviral drugs contribute to the development of these pathologies or potentiate HIV effects. We aimed to investigate whether azidothymidine (AZT), a drug still used by PWH in many resource-limited countries, alters or potentiates HIV-induced Alzheimer’s-like pathologies.

METHODS: Hu-PBL-NSG mice plasma/serum and brain tissues were analyzed to investigate the effects of HIV-1 infection and AZT treatment on viremia, immunosuppression, phospho-Tau, Aβ42, neuronal NeuN, endothelial claudin-5, ZO-1, and Aβ transporters [low-density lipoprotein receptor–related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE)] transcription, expression, and proteolytic cleavage. In vitro, we assessed the effects of HIV-1 Tat and AZT on Aβ42 aggregation, endothelial LRP1 and RAGE expression, Aβ uptake and transport.

RESULTS: HIV significantly increased brain phospho-Tau (serine199, threonine181, serine396), brain and plasma Aβ42, decreased LRP1, NeuN, claudin-5, ZO-1, and increased RAGE transcription and expression, increased soluble(s)LRP1 and decreased sRAGE. AZT treatment of infected animals decreased blood and brain viremia and reduced HIV-induced immunosuppression but had no effect on HIV-induced brain Aβ42, phospho-Tau, NeuN, claudin-5, ZO-1, LRP1 or RAGE transcription, expression, or cleavage. AZT treatment of non-infected animals significantly increased phospho-Tau in the brain somatosensory cortex, decreased LRP1, NeuN, claudin-5, and ZO-1, and increased RAGE transcription and expression, increased sLRP1 and decreased sRAGE. Tat decreased LRP1 and increased RAGE expression in brain endothelial cells, and AZT accentuated Tat-induced effects. AZT+Tat significantly increased Aβ aggregation and AZT significantly increased endothelial Aβ42 uptake/retention.

CONCLUSIONS: HIV and AZT independently dysregulate NeuN, claudin-5, ZO-1, LRP1 and RAGE transcription, expression, and proteolytic cleavage in hu-PBL-NSG mice. Such dysregulation of neuronal nuclei, endothelial tight junction proteins, and Aβ transporters could contribute to increased neurovascular injury and altered Aβ clearance following HIV infection and/or AZT treatment. In the presence of Tat, AZT increased Aβ aggregation. AZT also increased endothelial Aβ uptake/retention, which suggests that AZT may contribute to brain endothelium impairment and dysfunction.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-026-00807-4.},
}

@article {pmid42190844,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI reveals association between distal cerebral arterial flow and cognitive function in an aging population.},
journal = {Magnetic resonance imaging},
volume = {132},
number = {},
pages = {110702},
doi = {10.1016/j.mri.2026.110702},
pmid = {42190844},
issn = {1873-5894},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid42190921,
year = {2026},
author = {Bhasha, S and Chintada, V and Munikumar, M and Maddineni, J and Nagulavancha, R and Malempati, T and Gadda, SS and Sankepally, KKR and Adi, PJ},
title = {Targeting Tau-Mitochondrial Crosstalk in Alzheimer's Disease: Integrative Multi-Omics and Artificial Intelligence-Driven Tools for the Development of Disease-Modifying Therapeutics.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103186},
doi = {10.1016/j.arr.2026.103186},
pmid = {42190921},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating neurodegeneration. However, the molecular processes by which tau disease causes mitochondrial failure are poorly known. In this review, we discuss the tau-mitochondria interplay in AD and highlight how integrated multi-omics and computational approaches are boosting the development of disease-modifying treatments. We conducted an extensive evaluation of recent literature in key scientific databases related to tau biology, mitochondrial dysfunction, mitophagy, transcriptomics, proteomics, metabolomics, and computational drug development in AD. The results demonstrate that hyperphosphorylated tau leads to inhibition of mitochondrial transport, changes in membrane potential, impairment of oxidative phosphorylation and increased generation of reactive oxygen species (ROS). Multi-omics analyses show coordinated changes in molecular pathways affecting energy metabolism, synaptic maintenance and neuronal survival. Furthermore, computational and AI-based methods have enabled the recognition of novel tau-interacting proteins, mitophagy modulators and treatment candidates. The tau-mitochondrial interaction is a key pathogenic axis in Alzheimer's disease and provides prospective avenues for harnessing multi-omics and computational techniques to create mechanism-based treatments to restore mitochondrial function and synaptic integrity. This integrative paradigm provides a basis for next-generation precision therapies for neurodegenerative network dysfunction.},
}

@article {pmid42191654,
year = {2026},
author = {Isei, MO and Okeowo, OM and Okoye, CN and Sobodu, TO},
title = {Enhancing global Alzheimer's disease drug outcomes by comprehensive African data integration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452117},
doi = {10.1177/13872877261452117},
pmid = {42191654},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and continues to pose a substantial therapeutic challenge. Although recent advances in disease-modifying treatments targeting amyloid-β pathology have generated cautious optimism, their translational impact is limited by persistent gaps in population and geographic representation within clinical trials. African populations, the most genetically diverse worldwide, remain markedly underrepresented in AD genomic and therapeutic studies. This gap limits the identification of ancestry-specific genetic risk factors and differential treatment responses and may contribute to the high attrition rates observed across AD drug development pipelines. We examine how the limited inclusion of African cohorts restricts insights into AD pathobiology and reduces the external validity of emerging therapeutic strategies. We highlight opportunities arising from the systematic integration of African population and clinical data, which have the potential to reveal novel biological mechanisms and expand the global relevance of candidate interventions. Persistent barriers, including insufficient research infrastructure and frequent substitution of African American cohorts for indigenous African populations, continue to obscure population-specific variation and hinder the development of a representative evidence base. Advancing the field will require coordinated and context-appropriate recruitment strategies, predictive modeling approaches grounded in region-specific data, and long-term investment in research capacity across the continent. A globally representative scientific framework that captures the full spectrum of human genetic heterogeneity is essential for accelerating progress in AD drug development. Integrating African population and data into clinical research will strengthen scientific rigor, enhance generalizability, and facilitate the development of globally equitable therapeutic strategies.},
}

@article {pmid42191751,
year = {2026},
author = {Okda, M and El-Masry, SM and Helmy, MW and Abbas, H},
title = {Herbosomal nanocarriers using natural-origin surfactants: a quercetin-based strategy for Alzheimer's disease and oxidative-stress-driven neurodegeneration.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42191751},
issn = {2045-2322},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Surface-Active Agents/chemistry ; Animals ; Antioxidants/chemistry/pharmacology/administration & dosage ; *Drug Carriers/chemistry ; Neuroprotective Agents ; Polysorbates/chemistry ; *Nanoparticles/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction. Quercetin (QUE) is a multifunctional flavonoid with potent antioxidant and anti-inflammatory effects and proven neuroprotective, anticancer, antimicrobial, and hepatoprotective potential. However, its therapeutic translation, particularly in the management of Alzheimer's disease, is severely limited by low aqueous solubility, low bioavailability, and rapid metabolism. The current study aims to develop QUE-loaded herbosomes as an advanced phytophospholipid delivery system for AD treatment, with a focus on replacing the synthetic surfactant Tween 80 with natural-origin betaine surfactants to overcome the drawbacks of poor biocompatibility and chronic toxicity associated with conventional surfactants. QUE herbosomes were developed using the thin-film hydration method and evaluated for physicochemical characteristics, stability, and in vitro release behavior. Formulation variables were optimized to obtain herbosomal systems with favorable nanoscale properties and sustained drug release. DSC and FTIR analyses confirmed successful incorporation of quercetin within the vesicular structure. Compared with QUE suspension, the optimized QUE herbosomal formulations (F5 &F6) showed significantly higher effect in aluminum chloride-induced AD as evidenced by Behavioral testing, biochemical, and Histopathological analyses. These findings suggest that the developed QUE herbosomes with natural-origin surfactants offer a safe and biocompatible alternative to synthetic surfactant herbosomes, improving therapeutic outcomes in AD and holding promise for other oxidative stress-related neurodegenerative conditions.},
}

*Quercetin/chemistry/pharmacology/administration & dosage
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism
*Surface-Active Agents/chemistry
Animals
Antioxidants/chemistry/pharmacology/administration & dosage
*Drug Carriers/chemistry
Neuroprotective Agents
Polysorbates/chemistry
*Nanoparticles/chemistry

@article {pmid42191803,
year = {2026},
author = {Jalili, M and Babaei, P and Golshekan, M and Abedinzade, M and Andalib, S},
title = {Quercetin-loaded cellulose nanofibers improve memory, learning, and attenuate endoplasmic reticulum stress in a rat model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54595-w},
pmid = {42191803},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapy. This study evaluated the neuroprotective efficacy of quercetin-loaded cellulose nanofibers (QNP) in a streptozotocin (STZ)-induced AD rat model, focusing on memory impairment and endoplasmic reticulum (ER) stress. Forty-eight male Wistar rats were randomly allocated to six groups (n = 8): Control, AD model (ICV STZ 3 mg/kg on days 1 and 3), STZ + empty cellulose nanoparticles, STZ + free quercetin (10 mg/kg IP), STZ + QNP (10 mg/kg IP, equivalent quercetin dose), and STZ + donepezil (1 mg/kg IP) for 14 days. Morris water maze testing revealed that QNP significantly reduced escape latency during acquisition (31%, P < 0.001 vs. AD model) and increased time spent in the target quadrant during the probe trial (P < 0.01). QNP treatment resulted in significantly greater improvement compared to an equivalent dose of free quercetin (P < 0.05). RT-PCR demonstrated XBP-1 mRNA splicing exclusively in the AD model group, indicating activation of the unfolded protein response (UPR). Both free quercetin and QNP completely prevented this splicing, demonstrating potent suppression of ER stress. Cellulose nanofiber-mediated delivery significantly enhances quercetin's bioavailability and therapeutic efficacy, ameliorating cognitive deficits in AD likely via mitigation of ER stress. QNP represents a promising, biocompatible nano-therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42192197,
year = {2026},
author = {Liang, C and Zhou, Y and Zhuang, K and Wang, S and Zhong, L and Can, D and Lei, A and Li, H and Zhang, J and Leng, L},
title = {Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42192197},
issn = {1546-1726},
support = {2024J010001 to LL.//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.},
}

@article {pmid42192211,
year = {2026},
author = {Gaur, A and Wong, M and Chen, JJ and Kang, Y and Tahoulas, D and Jeor, K and Raguram, KH and Gallagher, D and Rapoport, M and Herrmann, N and Lanctôt, KL},
title = {Synaptic biomarkers in Alzheimer's disease dementia and mild cognitive impairment: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71501},
doi = {10.1002/alz.71501},
pmid = {42192211},
issn = {1552-5279},
support = {PTCG-20-700751/ALZ/Alzheimer's Association/United States ; /CAPMC/CIHR/Canada ; //Toronto Rehabilitation Institute/ ; ASRP #21-11//Alzheimer Society Research Program/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *Biomarkers/cerebrospinal fluid/blood ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *Synapses/metabolism ; Synaptosomal-Associated Protein 25/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by synaptopathy, a neuropathological feature that can contribute to underlying cognitive decline. Here, we evaluate potential cerebrospinal fluid (CSF) and blood-based synaptic biomarkers in AD dementia and its earliest clinical stage, mild cognitive impairment (MCI).

METHODS: Articles that measured a subset of CSF and/or blood-based synaptic biomarkers in AD dementia, MCI, and/or healthy controls were included. A random-effects model was used to determine standardized mean differences and 95% confidence intervals.

RESULTS: In total, 65 study cohorts were included for meta-analysis and 12 for qualitative review. Several CSF (synaptosomal-associated protein 25 [SNAP-25], growth-associated protein 43 [GAP-43], neuronal pentraxin receptor, neuronal pentraxin-1, neuronal pentraxin-2, synaptotagmin-1, syntaxin-1B, and vesicle-associated membrane protein 2) and blood-based (SNAP-25, GAP-43, and synaptotagmin-1) synaptic biomarkers were altered in AD dementia and/or MCI.

DISCUSSION: Further evaluation of these identified biomarkers may enrich our understanding of AD pathophysiology and disease trajectory, as well as inform future treatment interventions.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood
*Biomarkers/cerebrospinal fluid/blood
*Cognitive Dysfunction/cerebrospinal fluid/blood
*Synapses/metabolism
Synaptosomal-Associated Protein 25/cerebrospinal fluid

@article {pmid42192558,
year = {2026},
author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B},
title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70226},
pmid = {42192558},
issn = {2576-2095},
support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; },
abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.},
}

@article {pmid42192778,
year = {2026},
author = {Ramírez Hernández, E and Netzahualcoyotzi, C and Hurtado-Alvarado, G and Sánchez, JL and Pereyra Morales, A and Arredondo-Zamarripa, D and Hernández-Zimbrón, LF and Papy-Garcia, D and Guevara, J and Gutiérrez Ponce, N and Gomez-Henao, W and Garfias, Y and Ortiz Chavez, G and Zenteno, E},
title = {The Effect of Metabolic Syndrome on Alzheimer's Disease: Physical Activity as a Preventive and Therapeutic Measure.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050465},
pmid = {42192778},
issn = {2076-3425},
support = {PAPIIT IA208726//Universidad Nacional Autónoma de México/ ; PAPIIT IN222724//Universidad Nacional Autónoma de México/ ; PAPIIT IN204624//Universidad Nacional Autónoma de México/ ; },
abstract = {Epidemiological and clinical research on neurodegenerative diseases has shown that metabolic dysregulations increase the risk of developing Alzheimer's Disease (AD). Many metabolic changes can be grouped into metabolic syndrome (MetS), which is defined as the presence of three or more risk factors, including insulin resistance, hyperglycemia, hypertension, central obesity, and dyslipidemia. These changes cause systemic effects that are crucial in triggering neuroinflammation and neurodegeneration, key factors in AD development. All these factors impair energy metabolism in peripheral tissues and the brain by decreasing glucose utilization, leading to alterations in O-GlcNAcylation, glycosylation, mitochondrial function, oxidative stress, chronic inflammation, synaptic dysfunction, autophagy impairment, and blood-brain barrier (BBB) dysfunction. However, these factors are modified and largely influenced by lifestyle choices. A newer perspective emphasizes that regular exercise is vital for maintaining brain metabolism as we age. Current evidence suggests that engaging in physical activity for individuals with metabolic syndrome reduces their risk of Alzheimer's disease, enhances prognosis, and improves cognitive abilities. This review explores how metabolic syndrome relates to Alzheimer's and highlights possible strategies for prevention and treatment.},
}

@article {pmid42192839,
year = {2026},
author = {Valverde, HP and Clark, BJ and Hogeveen, J and Clark, VP},
title = {Noninvasive Brain Stimulation Techniques and Their Efficacy in Treating Cognition and Memory in Mild Cognitive Impairment and Alzheimer's Disease-A Systematic Review.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050527},
pmid = {42192839},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer's disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss.

METHODS: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included.

CONCLUSIONS: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer's disease in an aging population.},
}

@article {pmid42193043,
year = {2026},
author = {Zamzuri, ZE and Kamaruzzaman, MA and Teoh, SL and Yahaya, MF},
title = {A Review of the Effect of Peripheral Amyloid β on the Central Nervous System.},
journal = {Current issues in molecular biology},
volume = {48},
number = {5},
pages = {},
doi = {10.3390/cimb48050438},
pmid = {42193043},
issn = {1467-3045},
support = {FF-2025-443//Universiti Kebangsaan Malaysia Faculty of Medicine Fundamental Grants (GFFP)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid β (Aβ) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that Aβ metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating Aβ levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral Aβ, accounting for the majority of plasma Aβ under physiological and pathological conditions, while the liver and kidneys play critical roles in Aβ clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating Aβ, increasing its transport into the brain via blood-brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral Aβ entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of Aβ, differences between central and peripheral Aβ pools, mechanisms of Aβ transport across the BBB, pathological consequences of peripheral Aβ on the brain and emerging therapeutic strategies targeting peripheral Aβ metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment.},
}

@article {pmid42193260,
year = {2026},
author = {Virk, JP and Fernando, MG and Asih, PR and Martins, RN},
title = {Translational Feasibility of Curcumin for Treatment of Alzheimer's Disease: A Critical Appraisal of Clinical Challenges.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/antiox15050638},
pmid = {42193260},
issn = {2076-3921},
abstract = {The absence of robust and effective treatments for Alzheimer's disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for effective therapeutic strategies. Current treatments remain limited, with minimal impact on cognitive decline in symptomatic patients. Curcumin, the bioactive ingredient in turmeric, has taken precedence over other natural products due to its potent antioxidative and anti-inflammatory properties. Numerous publications have extensively reported on the therapeutic effect of curcumin in animal models of Alzheimer's disease. However, no curcumin formulation has demonstrated consistent clinical efficacy against Alzheimer's or other neurodegenerative diseases to date. Over the years, many critics have argued that curcumin's undesirable chemical properties, mainly low bioavailability and rapid metabolism, pose significant barriers to its therapeutic use to target the brain. Considerable funding and research effort on emerging technologies such as nanoparticles and intranasal delivery continue to drive curcumin preclinical and clinical trials, prompting reflection on the rationale for continued investment. This narrative review critically dissects this disconnect, arguing that many purported benefits remain insufficiently substantiated, and identifying important opportunities where future research may hold promise for an effective treatment.},
}

@article {pmid42193907,
year = {2026},
author = {Albensi, BC and Adlimoghaddam, A},
title = {Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100896},
pmid = {42193907},
issn = {2073-4409},
support = {AARF-22-967198/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Oxidative Phosphorylation/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Neurons/metabolism/drug effects/pathology ; Mice ; *Lithium/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Electron Transport Complex IV/metabolism ; Mice, Transgenic ; Energy Metabolism/drug effects ; Oxygen Consumption/drug effects ; Hippocampus/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in brain tissue; however, AD is multifactorial, and different etiopathogenic mechanisms involve factors that can affect mitochondrial function, which are associated with AD. While high-dose lithium is a well-established mood stabilizer, accumulating evidence suggests that low-dose lithium provides significant neuroprotection by reversing AD pathology, cognitive impairment, and inflammation. Despite these findings, there is limited information on how lithium affects brain energy metabolism. In the current study, we investigated the effect of lithium (0, 0.1, 1, and 10 mM) on mitochondrial function in AD neurons. Neuronal cells were isolated from the hippocampi of embryonic day 14-17 (E15-E17) control (C57BL/6) mice and 3xTg-AD mice. Mitochondrial oxygen consumption rate (OCR), mitochondrial Cytochrome C Oxidase (COX) activity, total ATP activity, and the expression of mitochondrial complex protein involved in oxidative phosphorylation (OXPHOS) were measured in control vs. 3xTg-AD in the presence and absence of lithium treatment. In the present study, lithium treatment significantly increased (p < 0.05) mitochondrial OCR, COX, total ATP, and levels of mitochondrial complex protein subunits (Complex I-V) in 3xTg-AD neurons. However, lithium had no effect on energy metabolism in control neurons. Together, these data indicate that lithium improves mitochondrial function under pathological states. Overall, these results have important implications for the treatment of disorders in which brain energy regulation is compromised, including AD. Particularly, our results highlight a role for lithium in regulating bioenergetics in early-stage AD and suggest that neuronal cells may be a crucial therapeutic target for preventing AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
*Oxidative Phosphorylation/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Neurons/metabolism/drug effects/pathology
Mice
*Lithium/pharmacology/therapeutic use
Mice, Inbred C57BL
Electron Transport Complex IV/metabolism
Mice, Transgenic
Energy Metabolism/drug effects
Oxygen Consumption/drug effects
Hippocampus/pathology/metabolism

@article {pmid42193936,
year = {2026},
author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK},
title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100928},
pmid = {42193936},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.},
}

Humans
*Neurodegenerative Diseases/therapy
Animals
Neuroprotective Agents/therapeutic use
Genetic Therapy

@article {pmid42195086,
year = {2026},
author = {André, Z and Kopániová, A and Gaštanová, B and Brandoburová, P and Režnáková, V and Fabian, M and Povinec, P and Hanes, J and Gmitterová, K},
title = {CSF Amyloid and Tau Biomarkers Distinguish Mixed from Vascular Dementia by Identifying Alzheimer's Disease Co-Pathology.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {5},
pages = {},
doi = {10.3390/medicina62050833},
pmid = {42195086},
issn = {1648-9144},
mesh = {Humans ; Biomarkers/cerebrospinal fluid/analysis ; *Dementia, Vascular/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid/analysis ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Amyloid beta-Peptides/cerebrospinal fluid/analysis ; Female ; Male ; Aged ; Mixed Dementias ; Diagnosis, Differential ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Aged, 80 and over ; Middle Aged ; },
abstract = {Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer's disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ1-42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ1-42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ1-42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ1-42, p-tau181/Aβ1-42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies.},
}

Humans
Biomarkers/cerebrospinal fluid/analysis
*Dementia, Vascular/cerebrospinal fluid/diagnosis
*tau Proteins/cerebrospinal fluid/analysis
*Alzheimer Disease/cerebrospinal fluid/diagnosis
*Amyloid beta-Peptides/cerebrospinal fluid/analysis
Female
Male
Aged
Mixed Dementias
Diagnosis, Differential
Peptide Fragments/cerebrospinal fluid
ROC Curve
Aged, 80 and over
Middle Aged

@article {pmid42195382,
year = {2026},
author = {Testa, C and Palmese, F and Boni, S and Domenicali, M and Lauretani, F},
title = {Clinical Trajectories of Neurodegenerative Diseases in Older Adults: A Three-Sphere Framework for Precision Geriatric Neurology.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/life16050827},
pmid = {42195382},
issn = {2075-1729},
abstract = {Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1-2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Parkinson's disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer's disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease.},
}

@article {pmid42196209,
year = {2026},
author = {Mouaimi, M and Metaxas, A and Kourti, M},
title = {The Emerging Role of Dimethyl Fumarate in Alzheimer's Disease-A Systematic Review of Available Preclinical Studies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104227},
pmid = {42196209},
issn = {1422-0067},
mesh = {*Dimethyl Fumarate/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Humans ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search of PubMed and Scopus (last search: December 2025) identified in vitro, in vivo, and combined preclinical studies assessing DMF in AD models. Studies were screened using predefined inclusion and exclusion criteria, and methodological quality was assessed using established tools. Results were synthesized narratively. Eighteen studies were ultimately included in the analysis. Across the included studies, DMF consistently activated the Nrf2 pathway, enhancing antioxidant and anti-inflammatory gene expression. DMF treatment reduced amyloid-β and tau protein levels, mitigated oxidative stress, and improved cognitive performance in animal models. However, the evidence is limited by heterogeneity in experimental models and methodological variability. In conclusion, preclinical evidence suggests DMF is a promising candidate for AD treatment by targeting oxidative stress and neuroinflammation via Nrf2 activation. Further preclinical studies, particularly on ferroptosis mechanisms, and well-designed clinical studies are warranted to clarify its full therapeutic potential. This review was not registered and the authors received no funding.},
}

*Dimethyl Fumarate/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Humans
NF-E2-Related Factor 2/metabolism
Oxidative Stress/drug effects
Antioxidants/pharmacology/therapeutic use
Disease Models, Animal
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42196212,
year = {2026},
author = {Jóźwiak-Bębenista, M and Stasiak, A and Sienkiewicz, M and Kwiatkowski, P and Kowalczyk, E},
title = {Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging-From Depression to Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104229},
pmid = {42196212},
issn = {1422-0067},
support = {503/1-108-01/503-11-001//Medical University of Lodz/ ; },
mesh = {Humans ; *Aging/drug effects ; *Inflammation/drug therapy ; *Neurodegenerative Diseases/drug therapy ; *Depression/drug therapy ; *Psilocybin/therapeutic use/pharmacology ; Animals ; Aged ; *Hallucinogens/therapeutic use/pharmacology ; },
abstract = {Aging is associated with chronic, low-grade inflammation ("inflammaging"), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer's disease, and Parkinson's disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin's neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.},
}

Humans
*Aging/drug effects
*Inflammation/drug therapy
*Neurodegenerative Diseases/drug therapy
*Depression/drug therapy
*Psilocybin/therapeutic use/pharmacology
Animals
Aged
*Hallucinogens/therapeutic use/pharmacology

@article {pmid42196227,
year = {2026},
author = {Kasprzak, A},
title = {Somatostatin in Aging: Correlations with Selected Central Nervous System and Gastrointestinal Tract Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104244},
pmid = {42196227},
issn = {1422-0067},
mesh = {Humans ; *Aging/metabolism ; *Somatostatin/metabolism ; Animals ; *Gastrointestinal Diseases/metabolism ; *Central Nervous System/metabolism ; },
abstract = {The hypothalamic-pituitary-somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer's and Parkinson's diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers).},
}

Humans
*Aging/metabolism
*Somatostatin/metabolism
Animals
*Gastrointestinal Diseases/metabolism
*Central Nervous System/metabolism

@article {pmid42196498,
year = {2026},
author = {Bianchi, VE and Visbal, LC and Devesa, J},
title = {Growth Hormone and Brain Regeneration: Evidence from Clinical Studies in Dementia, Traumatic Brain Injury, and Stroke: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104521},
pmid = {42196498},
issn = {1422-0067},
mesh = {Humans ; *Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology ; *Stroke/drug therapy/metabolism/physiopathology ; *Dementia/drug therapy/metabolism ; *Growth Hormone/therapeutic use/metabolism/pharmacology ; Animals ; *Brain/drug effects/physiology/metabolism ; Insulin-Like Growth Factor I/metabolism ; *Regeneration/drug effects ; },
abstract = {Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer's disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: "GH and dementia," "GH and Alzheimer's disease," "GH and TBI," and "GH and stroke." Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer's disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results.},
}

Humans
*Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology
*Stroke/drug therapy/metabolism/physiopathology
*Dementia/drug therapy/metabolism
*Growth Hormone/therapeutic use/metabolism/pharmacology
Animals
*Brain/drug effects/physiology/metabolism
Insulin-Like Growth Factor I/metabolism
*Regeneration/drug effects

@article {pmid42196596,
year = {2026},
author = {Hasan, I and Tang, X and Xu, J},
title = {Glial Cells in Behavioral and Psychological Symptoms of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104621},
pmid = {42196596},
issn = {1422-0067},
support = {82173798//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/pathology/metabolism ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Oligodendroglia/metabolism/pathology ; },
abstract = {Behavioral and psychological symptoms of dementia (BPSD) affect the majority of patients with Alzheimer's disease (AD), substantially increasing caregiver burden and the likelihood of institutionalization. The clinical management of BPSD remains challenging because of its poorly understood pathogenesis, the limited efficacy of conventional interventions, and significant safety concerns associated with current treatments. These limitations underscore the urgent need to identify novel therapeutic targets and develop glia-centered treatment strategies. As essential components of the central nervous system, glial cells maintain neural homeostasis, regulate neurotransmission, and mediate neuroinflammatory responses. Increasing evidence suggests that glial dysfunction contributes to the development of BPSD, thereby linking AD neuropathology and neuropsychiatric symptoms. Aberrant microglial activation, astrocytic dysfunction, and oligodendrocyte injury collectively compromise neural circuit integrity, disrupt neurotransmitter balance, and impair neuron-glia communication, ultimately promoting the progression of diverse BPSDs. Given the critical role of glial cells in regulating neurotransmitter systems, the dysregulation of which is closely associated with BPSD, this review summarizes the involvement of glial cells in BPSD, elucidates the underlying molecular mechanisms, and discusses recent advances in glia-based therapeutic strategies, thereby providing insights into the pathogenesis of BPSD in AD.},
}

Humans
*Alzheimer Disease/psychology/pathology/metabolism
*Neuroglia/metabolism/pathology
Animals
Microglia/metabolism/pathology
Astrocytes/metabolism/pathology
Oligodendroglia/metabolism/pathology

@article {pmid42196607,
year = {2026},
author = {Wind-Mark, K and Kunze, LH and Willem, M and Palumbo, G and Giudici, C and Nuscher, B and Boening, G and Gildehaus, FJ and Lindner, S and Werner, RA and Franzmeier, N and Gnörich, JS and Brendel, M and Zatcepin, A},
title = {Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104632},
pmid = {42196607},
issn = {1422-0067},
support = {EXC 2145 SyNergy - ID 390857198//German Research Foundation/ ; Medical & Clinician Scientist Program (MCSP)//Ludwig Maximilian University of Munich/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Mice ; Positron-Emission Tomography ; Disease Models, Animal ; Pioglitazone/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy/diagnostic imaging ; Receptors, GABA/metabolism ; *Antibodies, Monoclonal/pharmacology/therapeutic use ; *Immunomodulation/drug effects ; PPAR-gamma Agonists ; Mice, Transgenic ; Microglia/metabolism/drug effects ; Brain ; },
abstract = {Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer's disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. App[NL-G-F] knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.},
}

Animals
*Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Mice
Positron-Emission Tomography
Disease Models, Animal
Pioglitazone/pharmacology/therapeutic use
*Neuroinflammatory Diseases/drug therapy/diagnostic imaging
Receptors, GABA/metabolism
*Antibodies, Monoclonal/pharmacology/therapeutic use
*Immunomodulation/drug effects
PPAR-gamma Agonists
Mice, Transgenic
Microglia/metabolism/drug effects
Brain

@article {pmid42198335,
year = {2026},
author = {Lu, H and Yu, Y and Yang, Y and Li, H and Li, Y and Yu, T and Wang, S and Li, F and Cheng, X},
title = {Ginsenoside Rg1 Ameliorates the Learning and Memory Deficits of 5xFAD Mice by Inhibiting CCR3 Activity: Insights from In Vivo and In Vitro Investigations.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050661},
pmid = {42198335},
issn = {1424-8247},
support = {No.82374062//National Natural Science Foundation of China/ ; YDZX2023003//Central government-guided special fund project for local scientific and technological development/ ; KYZK2024Q24//Shandong University of Traditional Chinese Medicine Youth Science Research Fund Project/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1-40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10[-5] mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.},
}

@article {pmid42198353,
year = {2026},
author = {Skroban, J and Kruk-Słomka, M and Popiołek, Ł},
title = {Exploring Acylhydrazones' Properties Against Neurodegenerative Diseases and Other Clinical Applications: A Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050679},
pmid = {42198353},
issn = {1424-8247},
abstract = {Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020-2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs.},
}

@article {pmid42198361,
year = {2026},
author = {Silva, R and Monteiro, J and Ramalho, MJ and Andrade, S and Loureiro, JA and Pereira, MC},
title = {Advances in Strategies to Transport Nanoparticles Across the Blood-Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050685},
pmid = {42198361},
issn = {1424-8247},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive dementia, constituting one of the leading causes of global mortality. Although the current treatments help attenuate the symptoms associated with AD, they are unable to stop the long-term progression of the disease, and consequently, no cure exists. One of the main reasons for the lack of cure and, therefore, one of the biggest challenges in its treatment, is the blood-brain barrier (BBB). This protective barrier limits the entry of foreign substances, including drugs, into the central nervous system. Different types of engineered nanoparticles (NPs) have been demonstrated to be able to penetrate this barrier and serve as efficient drug delivery systems (DDS) into the brain, making them a promising solution for future therapeutic development. Therefore, the purpose of this paper is to provide valuable insights into challenges faced by DDS in treating AD, highlight the nanotechnology-based approach, and discuss the advances in strategies being employed to enhance the crossing of NPs through the BBB. Furthermore, some up-to-date NP systems are presented, along with the latest therapeutic agents targeting AD, and finally, it underscores innovative approaches under investigation. Ultimately, the barriers hindering the clinical translation of NP-based strategies into human patients are discussed.},
}

@article {pmid42198444,
year = {2026},
author = {Badawi, GA and Shaaban, RS and Almutairi, JA and El-Masry, TA and Zaki, HF and Ibrahim, SM},
title = {Physical Exercise Enhances Melatonin Effect in D-Galactose/Aluminum Chloride-Induced Alzheimer's Disease of Ovariectomized Rats: Irisin Induction Associated with Upregulation of PPAR-γ/IGF-1/BDNF and Decreasing TNF-α/p38-MAPK/NLRP3/GFAP Pathway.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050770},
pmid = {42198444},
issn = {1424-8247},
support = {PNURSP2026R892//Princess Nourah bint Abdulrahman University Researchers Supporting Project/ ; },
abstract = {Background: Postmenopausal women are at high risk of Alzheimer's disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl3 (60 and 10 mg/kg, respectively) for 42 days. Group III-V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway.},
}

@article {pmid42199014,
year = {2026},
author = {Hao, L and Xing, Y and Han, Y},
title = {Status of diagnosis, treatment, and care of Alzheimer's disease continuum in China: A survey-based analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261453551},
doi = {10.1177/13872877261453551},
pmid = {42199014},
issn = {1875-8908},
abstract = {BackgroundThe 2018 NIA-AA framework outlines a six-stage continuum from asymptomatic individuals to severe Alzheimer's disease (AD) dementia, but most Chinese research still focuses on dementia or broad diagnostic categories.ObjectiveTo map diagnosis, treatment, and care patterns across all six AD clinical stages in China and identify demographic, clinical, treatment and care-related factors associated with disease stage.MethodsWe conducted a nationwide, open online survey via official media channels targeting patients with clinician-confirmed AD and their caregivers. Data were collected via Questionnaire Star. Descriptive analyses, group comparisons, and ordinal logistic regression were performed to examine factors associated with NIA-AA stage.ResultsA total of 1116 valid responses were analyzed. Most participants were at Stage 2 or higher, with distribution of 0.4%, 9.1%, 16.0%, 24.8%, 26.6%, and 23.0%, across Stage 1-6. Overall, 64.5% had been diagnosed within five years. Neurology (66.4%) and memory clinics (19.2%) were the most frequently visited departments. Donepezil (52.2%) and Memantine (38.8%) were the most common medications, while 34.5% reported engaging in non-pharmacological interventions. Only 1.9% of patients receiving professional dementia institutional care. In logistic regression, disease duration (OR = 0.724, p = 0.006), stage at first outpatient visit (OR= 1.843, p < 0.001), and Donepezil use (OR = 1.394, p = 0.003) were independently associated with current NIA-AA stage.ConclusionsThis study provides the first nationwide, real-world description of diagnosis, treatment, and care across all NIA-AA stages in China. The findings highlight the need for improved primary-care screening, expanded memory-clinic access, and structured caregiver support to promote earlier detection and more equitable, stage-appropriate management of AD.},
}

@article {pmid42199025,
year = {2026},
author = {Wang, Y},
title = {Mesenchymal stem cell-mediated regulation of neuroinflammation and amyloid-β clearance: A promising therapeutic strategy for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451894},
doi = {10.1177/13872877261451894},
pmid = {42199025},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline. Its pathogenesis is complex, involving multiple pathological processes, including amyloid-β (Aβ) deposition, neuroinflammation, and synaptic dysfunction. In recent years, the role of mesenchymal stem cells (MSCs) in AD therapy has garnered significant attention. MSCs, through their multi-directional differentiation potential and paracrine effects, exhibit remarkable neuroprotective and anti-inflammatory properties, influencing AD progression. This review summarizes the potential mechanisms and effects of MSCs in AD treatment and explores precision therapeutic strategies based on MSC modulation.},
}

@article {pmid42199075,
year = {2026},
author = {Jin, L and Wang, X and Song, F and Hou, J and Bi, Y and Wen, X and Wang, X and Lai, F and Cheng, A},
title = {Quantitative AV-45 PET imaging for assessing treatment response to lecanemab and deep cervical lymphatic-venous anastomosis in Alzheimer's disease.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
doi = {10.1097/MNM.0000000000002184},
pmid = {42199075},
issn = {1473-5628},
support = {no. 82001862//National Natural Science Founda tion of China/ ; },
abstract = {OBJECTIVES: This study aimed to validate the clinical utility of visual and software-based quantitative AV-45 PET analyses and compare treatment effects between lecanemab and deep cervical lymphatic-venous anastomosis (dcLVA).

METHODS: This retrospective cohort study included Alzheimer's disease patients who received 6-month lecanemab therapy or dcLVA surgery between July 2024 and 2025. AV-45 PET was performed 1 week before and 6 months after treatment. Standardized uptake value ratios (SUVRs) and centiloids (CLs) were obtained using visual and quantitative analyses. Agreement was assessed using Cohen's κ and intraclass correlation coefficients (ICC). Receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Logistic regression used Informant Questionnaire on Cognitive Decline in the Elderly score greater than or equal to 3.3 as the outcome.

RESULTS: Baseline characteristics were comparable between groups (all P > 0.05). Visual assessment showed good agreement with centiloid quantification (κ = 0.72, ICC = 0.663). ROC analysis identified ΔCL as the optimal marker (area under the curve = 0.764, P = 0.026), with a cutoff of -11.5%. ΔCL ≥ -11.5% independently predicted cognitive decline in the lecanemab group (odds ratio = 10.281, 95% confidence interval = 1.289-82.005; P = 0.028). Cognitive decline was less frequent in the lecanemab group (23.5 vs. 81.8%; P < 0.001). ΔCL differed significantly between groups (P = 0.006), whereas ΔSUVR did not.

CONCLUSION: Visual and centiloid-based AV-45 PET analyses show good concordance for monitoring Alzheimer's disease treatment response. ΔCL is a robust marker of lecanemab efficacy, which is superior to dcLVA in reducing amyloid-β burden and delaying cognitive decline.},
}

@article {pmid42199126,
year = {2026},
author = {Wang, Y and Wang, Z and Zhao, J and Zhou, Y and Wei, D and Zhao, J and Sun, Z and Jiang, W},
title = {Mitochondrial transfer: A comprehensive analysis of mechanistic insights, preclinical applications, and technological innovations.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01156},
pmid = {42199126},
issn = {1673-5374},
abstract = {Mitochondrial transfer, the intercellular exchange of functional mitochondria, is crucial for maintaining cellular homeostasis and promoting tissue repair, particularly in neurological disorders associated with mitochondrial dysfunction. This review addresses the mechanisms through which mitochondrial transfer occurs, including tunneling nanotubes, extracellular vesicles, gap junction channels, and cell fusion. Mitochondrial transfer and transplantation have demonstrated positive therapeutic effects in various disease models, such as cerebral hemorrhage, ischemic stroke, Alzheimer's disease, and multiple sclerosis. Exogenous mitochondria can integrate into recipient cells, enhancing adenosine triphosphate production, restoring redox balance, and improving cellular survival under stress conditions. However, clinical translation faces significant hurdles, including immune rejection, limited recipient cell uptake capacity, a lack of standardized manufacturing protocols, and unresolved ethical concerns regarding mitochondrial sourcing. To address these challenges, cutting-edge biotechnological strategies, such as mitochondrial surface modification, nanocarrier-based delivery, biomaterial-assisted transplantation, and the use of engineered vesicles, are being developed to enhance the precision, stability, and biocompatibility of mitochondrial delivery. Furthermore, innovative approaches, including CRISPR-based genome editing, 3D-bioprinted tissue models, and artificial intelligence-assisted predictive platforms, are being explored to enhance mitochondrial function and delivery efficiency. Current strategies to harness mitochondrial transfer include pharmacological agents that enhance mitochondrial dynamics, stem cell-based delivery of healthy mitochondria, and the aforementioned bioengineered platforms. In conclusion, the integration of mitochondrial transfer as a groundbreaking treatment option for neurological disorders relies on addressing two to three fundamental challenges. These include the establishment of standardized and scalable protocols for production and quality control, formulating approaches to minimize immune reactions and improve the efficiency of mitochondrial integration, and creating a well-defined ethical and regulatory framework for sourcing and utilizing mitochondria. The primary contribution of this work lies in its integrated analysis of mechanistic insights, preclinical applications, and technological innovations, providing a consolidated roadmap for advancing mitochondrial transplantation from bench to bedside.},
}

@article {pmid42199136,
year = {2026},
author = {Huang, Z and Zhu, Y and Li, X and Lei, X and Tang, L and Wen, D and Yao, S and Gong, J and Zang, G and Guo, Z},
title = {Dopamine, glutamate, and gamma-aminobutyric acid: Key hubs in neurotransmitters, signal transduction, and cognitive dysfunction.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00849},
pmid = {42199136},
issn = {1673-5374},
abstract = {Neurotransmitters such as dopamine, glutamate, and gamma-aminobutyric acid (GABA) play crucial roles in regulating cognitive functions including learning, memory, and executive control. Dysregulation in synthesis, release, and metabolism of these neurotransmitters is implicated in the pathogenesis of various neurological disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia, leading to significant cognitive impairment. Recent research highlights that dopamine modulates reward processing, motivation, and memory through its synthesis via tyrosine hydroxylase and reuptake via the dopamine transporter. Glutamate, the primary excitatory neurotransmitter, mediates synaptic plasticity and cognitive processes through ionotropic and metabotropic receptors, while gamma-aminobutyric acid maintains inhibitory balance via GABA A and GABA B receptors. Notedly, interactions among these neurotransmitters, such as dopamine-Glu cross-talk through N-methyl-D-aspartate and dopamine receptors, and GABAergic regulation of dopaminergic activity, are critical for cognitive function. Existing detection techniques, including microdialysis, electrochemical sensors, and genetically encoded indicators, have advanced our understanding but still lack the spatiotemporal resolution needed to fully capture dynamic neurotransmitter interactions in real time. Although pharmacological interventions targeting these systems (e.g., L-3,4-dihydroxyphenylalanine, ketamine, GABAergic modulators) show potential, clinical applications are limited by significant side effects and variable efficacy. In summary, a multi-target approach, combining advanced detection methods with a deeper understanding of neurotransmitter crosstalk, may pave the way for more effective diagnostic and treatment interventions for cognitive disorders.},
}

@article {pmid42182271,
year = {2026},
author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W},
title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.12.724591},
pmid = {42182271},
issn = {2692-8205},
abstract = {UNLABELLED: Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimer's disease (AD) incidence (12-78%) among Bacillus Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.

ONE SENTENCE SUMMARY: BCG therapy prevents tauopathy in PS19 mouse model.},
}

@article {pmid42182561,
year = {2026},
author = {Iizuka, T and Watanabe, T and Kameyama, M},
title = {Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801267},
pmid = {42182561},
issn = {1663-4365},
abstract = {BACKGROUND: Anti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer's disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.

METHODS: We conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial [18]F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using [123]I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis.

RESULTS: All participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal.

CONCLUSION: In this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.},
}

@article {pmid42183357,
year = {2026},
author = {Grabowska, ME and Chen, R and Zhou, Y and Vaidya, AU and Zhong, X and Guardo, C and Dickson, AL and Babanejad, M and Yan, C and Xin, Y and Mundo, S and Peterson, JF and Li, L and Embí, P and Feng, Q and Eaton, J and Wen, Z and Li, B and Wei, WQ},
title = {Integrating genetically predicted transcriptomic signatures with longitudinal real-world data enables scalable drug repurposing for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9518587/v1},
pmid = {42183357},
issn = {2693-5015},
abstract = {Drug repurposing offers a potential strategy to expand treatment options for conditions with limited therapies, but advancing repurposing candidates toward clinical implementation remains a challenge. Large-scale data, together with advanced genetic and epidemiological methods, may help address this gap. Here, we present an integrative digital medicine approach that combines genetically predicted transcriptomic signatures and perturbation screening for candidate identification with multi-cohort real-world validation for systematic evaluation of prioritized candidates. We applied this approach to Alzheimer's disease (AD), a disease with substantial unmet clinical need and persistent difficulty in developing effective therapies. We constructed AD signatures from genetically predicted expression changes across bulk tissues and microglia, then queried Connectivity Map profiles to identify compounds predicted to oppose these signatures. Aspirin emerged as a reproducible candidate across multiple signatures and underwent further evaluation. We then examined its association with incident AD in longitudinal electronic health record data from Vanderbilt University Medical Center and the NIH All of Us Research Program, as well as national insurance claims data. Across independent cohorts, aspirin initiation before age 65 was consistently associated with lower risk of incident AD, with signals suggesting that cumulative exposure and APOE ε4 status may influence effect size. Transcriptomic analysis of human cortical organoids provided additional experimental support, showing that aspirin more strongly opposed AD-related neuronal pathway alterations in wild-type organoids than in an organoid model of AD. This integrative approach offers a scalable strategy for genetically informed drug repurposing that bridges candidate discovery and clinical evaluation.},
}

@article {pmid42184087,
year = {2026},
author = {Abdelaziz, AM and Shokr, MM and Fathy, MK and Fawzy, MN},
title = {Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42184087},
issn = {1559-1166},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *ADP-ribosyl Cyclase 1/metabolism ; *Mitochondria/metabolism ; *rho GTP-Binding Proteins/metabolism ; Animals ; *Neurons/metabolism ; *Astrocytes/metabolism ; *Membrane Glycoproteins/metabolism ; *Mitochondrial Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca[2+] signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca[2+] overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*ADP-ribosyl Cyclase 1/metabolism
*Mitochondria/metabolism
*rho GTP-Binding Proteins/metabolism
Animals
*Neurons/metabolism
*Astrocytes/metabolism
*Membrane Glycoproteins/metabolism
*Mitochondrial Proteins/metabolism